Pyrrolidine oxadiazole- and thiadiazole oxime derivatives being oxytocin receptor antagonists

ABSTRACT

The present invention is related to pyrrolidine oxadiazole and thiadiazole derivatives for use as pharmaceutically active compounds, as well as pharmaceutical formulations containing such pyrrolidine oxadiazole derivatives. Said pyrrolidine derivatives are useful in the treatment and/or prevention of preterm labor, premature birth and dysmenorrhea. In particular, the present invention is related to pyrrolidine derivatives displaying a substantial modulatory, notably an antagonist activity of the oxytocin receptor. More preferably, said compounds are useful in the treatment and/or prevention of disease states mediated by oxytocin, including preterm labor, premature birth and dysmenorrhea. The present invention is furthermore related to novel pyrrolidine derivatives as well as to methods of their preparation. (I) B is a oxadiazole or thiadiazole group

This application is a 371 of PCT/EP02/06629, filed on Jun. 14, 2002.This application claims priority under 35 U.S.C. 119 (a–d) to foreignapplication EPO 01113632.2 filed on Jun. 18, 2001.

FIELD OF THE INVENTION

The present invention is related to new pyrrolidine oxadiazole andpyrrolidine thiadiazole derivatives, in particular for use asmedicaments, as well as pharmaceutical formulations containing suchpyrrolidine derivatives. Said pyrrolidine derivatives are useful in thetreatment and/or prevention of preterm labor, premature birth anddysmenorrhea. Preferably, the pyrrolidine derivatives display amodulatory, notably an antagonist activity of the oxytocin receptor.More preferably, said compounds are useful in the treatment and/orprevention of disease states mediated by oxytocin, including pretermlabor, premature birth and dysmenorrhea.

BACKGROUND OF THE INVENTION

In the field of obstetrics, one of the most important problems is themanagement of preterm labor and premature birth as they represent amajor cause of perinatal morbidity and mortality.

For the treatment of preterm labor the use of magnesium sulfate andethanol has been suggested. However, magnesium sulfate at plasmaconcentrations above the therapeutic range of 4 to 8 mg/dL can causeinhibition of cardiac conduction and neuromuscular transmission,respiratory depression and cardiac arrest, thus making this agentunsuitable notably when the renal function is impaired.

Ethanol is effective in preventing premature labor, but it does notproduce a corresponding reduction in the incidence of fetal respiratorydistress. Also, ethanol is assumed to have a negative impact on thefetus.

Two further therapeutical agents fall into either of the groups of:

-   -   a) β2-adrenergic agonists, or    -   b) oxytocin antagonists.

The β2-adrenergic receptor generally causes an inhibitory action withinthe cells wherein it is expressed (muscles, heart, uterus etc).β2-adrenergic agonists are used to activate said inhibitory action ofthe receptor. Hence, β2-adrenergic agonists are sympathomimeticswhich—among others—inhibit uterine contractility. Known β2-adrenergicagonists for the treatment of preterm labor are Ritodrine, Terbutalineand Albuterol.

Ritodrine (i.e.(R*,S*)-4-Hydroxy-.alpha.-[1-[[2-(4-hydroxyphenyl)ethyl]amino]ethyl]benzenemethanol;see U.S. Pat. No. 3,410,944 of N. V. Philips) is the leadingβ₂-adrenergic agonist but causes a number of cardiovascular andmetabolic side effects in the mother, including tachycardia, increasedrenin secretion, hyperglycemia (and reactive hypoglycemia in theinfant).

Terbutaline (i.e.5-[2-[(1,1-Dimethylethyl)amino]-1-hydroxyethyl]-1,3-benzenediol, U.S.Pat. No. 3,937,838, Draco) and Albuterol(α¹-[[(1,1-Dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol;U.S. Pat. No. 3,644,353, Allen and Hanburys) are further β₂-adrenergicagonists and have side effects similar to those of Ritodrine.

A more recent approach of treating preterm labor consists in the use ofoxytocin antagonists.

Oxytocin (OT) is a peptide hormone and causes the contraction of theuterus of mammals during labor. The corresponding oxytocin receptor issimilar to V_(1a) and V₂ vasopressin receptors and acts via a Gprotein-coupled receptor, coupled to activation of phospholipase C andincreases in IP₃ that release Ca²⁺ from intracellular stores. Theincreases in intracellular calcium that ensue lead to increasedcontraction of smooth muscle via activation of myosin light chainkinase. Oxytocin (OT) receptors increase dramatically during the courseof pregnancy. The concentration of OT receptors has been shown tocorrelate with spontaneous uterine activity (M. Maggi et al. J. Clin.Endocrinol Metabol; 70; 1142, 1990). In the last few years, evidence hasaccumulated to strongly suggest that the hormone oxytocin may be aphysiological initiator of labor in several mammalian species includinghumans. Furthermore, oxytocin is believed to exert this effect in twodifferent parts:

-   -   by directly contracting the uterine myometrium and    -   by enhancing the synthesis and release of contractile        prostaglandins from the uterine endometrium/decidua. These        prostaglandins may, in addition, be important in the cervical        ripening process.

By these mechanisms, the process of labor (term and preterm) isinitiated by a heightened sensitivity of the uterus to oxytocin,resulting in part as a result of an increase in the number of oxytocinreceptors in this tissue.

By blocking oxytocin, the direct (contractile) and indirect (enhancedprostaglandin synthesis) effects of oxytocin on the uterus may beachieved. An oxytocin blocker, or antagonist, is therefore assumed to bemore efficacious for treating preterm labor than current regimens.

Atosiban (i.e. oxytocin, 1-(3-mercaptopropanoicacid)-2-(O-ethyl-D-tyrosine)-4-L-threonine-8-L-ornithine) is a cyclicpentapeptide which is the best known OT antagonist (WO 9501368, FerringA B; J. Reprod. Fertil., 101(2), 345–52 (English) 1994; Am. J. Obstet.Gynecol., 170(2), 474–8 (English) 1994). The principal drawback to theuse of peptide antagonists like atosiban is the problem of low oralbioavailability resulting from intestinal degradation. Hence, they mustbe administered parenterally.

Also, WO 96/22775 and U.S. Pat. No. 5,756,497 (Merck) disclosebenzoxazinyl-piperidines or benzoxazinones as OT receptor antagonists.Indanylpiperidines and tolyl-piperazines are reported by Evans et al. inJ. Med. Chem., 35, 3919 (1992) as being orally deliverable OTantagonists

It has now been found that compounds of the present invention areantagonists of oxytocin and bind to the oxytocin receptor. When theoxytocin receptor is bound by the compounds of the present invention,oxytocin is antagonized by being blocked from its receptor and thusbeing unable to exert its biologic or pharmacologic effects. Thecompounds of the present invention are therefore useful in the treatmentand prevention of preterm labor and premature birth. The compounds arealso useful for stoppage of labor preparatory to cesarean delivery. Inparticular the compounds of the present invention are useful in thetreatment and prevention of oxytocin-related disorders of animals,preferably mammals and especially humans. It is another purpose of thisinvention to provide a method of antagonizing the functions of oxytocinin disease states in mammals. It is also a purpose of this invention todevelop a method of preventing or treating the oxytocin-relateddisorders of preterm labor by antagonizing the binding of oxytocin toits receptor.

The compounds of the present invention are also useful in the treatmentof dysmenorrhea which may be defined as a cyclic pain associated withmenses during ovulatory cycles. The pain is thought to result fromuterine contractions and ischemia, probably mediated by the effect ofprostaglandins produced in the secretory endometrium. By blocking boththe direct and indirect effects of oxytocin on the uterus, an oxytocinantagonist is more efficacious for treating dysmenorrhea than currentregimens.

DESCRIPTION OF THE INVENTION

The following paragraphs provide definitions of the various chemicalmoieties that make up the compounds according to the invention and areintended to apply uniformly throughout the specification and claimsunless an otherwise expressly set out definition provides a broaderdefinition.

“C₁–C₆-alkyl” refers to monovalent alkyl groups having 1 to 6 carbonatoms. This term is exemplified by groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl and thelike.

“Aryl” refers to an unsaturated aromatic carbocyclic group of from 6 to14 carbon atoms having a single ring (e.g., phenyl) or multiplecondensed rings (e.g., naphthyl). Preferred aryl include phenyl,naphthyl, phenantrenyl and the like.

“C₁–C₆-alkyl aryl” refers to C₁–C₆-alkyl groups having an arylsubstituent, including benzyl, phenethyl and the like.

“Heteroaryl” refers to a monocyclic heteroaromatic, or a bicyclic or atricyclic fused-ring heteroaromatic group. Particular examples ofheteroaromatic groups include optionally substituted pyridyl, pyrrolyl,furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl,[2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl,isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl,imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl,quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl,pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl,quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl,5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl,xanthenyl or benzoquinolyl.

“C₁–C₆-alkyl heteroaryl” refers to C₁–C₆-alkyl groups having aheteroaryl substituent, including 2-furylmethyl, 2-thienylmethyl,2-(1H-indol-3-yl)ethyl and the like.

“C₂–C₆-alkenyl” refers to alkenyl groups preferably having from 2 to 6carbon atoms and having at least 1 or 2 sites of alkenyl unsaturation.Preferable alkenyl groups include ethenyl (—CH═CH₂), n-2-propenyl(allyl, —CH₂CH═CH₂) and the like.

“C₂–C₆-alkenyl aryl” refers to C₂–C₆-alkenyl groups having an arylsubstituent, including 2-phenylvinyl and the like.

“C₂–C₆-alkenyl heteroaryl” refers to C₂–C₆-alkenyl groups having aheteroaryl substituent, including 2-(3-pyridinyl)vinyl and the like.

“C₂–C₆-alkynyl” refers to alkynyl groups preferably having from 2 to 6carbon atoms and having at least 1–2 sites of alkynyl unsaturation,preferred alkynyl groups include ethynyl (—C≡CH), propargyl (—CH₂C≡CH),and the like.

“C₂–C₆-alkyl aryl” refers to C₂–C₆-alkynyl groups having an arylsubstituent, including phenylethynyl and the like.

“C₂–C₆-alkynyl heteroaryl” refers to C₂–C₆-alkynyl groups having aheteroaryl substituent, including 2-thienylethynyl and the like.

“C₃–C₈-cycloalkyl” refers to a saturated carbocyclic group of from 3 to8 carbon atoms having a single ring (e.g., cyclohexyl) or multiplecondensed rings (e.g., norbornyl). Preferred cycloalkyl includecyclopentyl, cyclohexyl, norbornyl and the like.

“C₁–C₆-alkyl cycloalkyl” refers to C₁–C₆-alkyl groups having acycloalkyl substituent, including cyclohexylmethyl, cyclopentylpropyl,and the like.

“heterocycloalkyl” refers to a C3–C8-cycloalkyl group according to thedefinition above, in which up to 3 carbon atoms are replaced byheteroatoms chosen from the group consisting of O, S, NR, R beingdefined as hydrogen or methyl. Preferred heterocycloalkyl includepyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine, andthe like.

“C₁–C₆-alkyl heterocycloalkyl” refers to C₁–C₆-alkyl groups having aheterocycloalkyl substituent, including 2-(1-pyrrolidinyl)ethyl,4-morpholinylmethyl, (1-methyl-4-piperidinyl)methyl and the like.

“Carboxy” refers to the group —C(O)OH.

“C₁–C₆-alkyl carboxy” refers to C₁–C₆-alkyl groups having an carboxysubstituent, including 2-carboxyethyl and the like.

“Acyl” refers to the group —C(O)R where R includes H, “C₁–C₆-alkyl”,“C₂–C₆-alkenyl”, “C₂–C₆-alkynyl”, “C₃–C₈-cycloalkyl”,heterocycloalkyl“heterocycloalkyl”, “aryl”, “heteroaryl”, “C₁–C₆-alkylaryl” or “C₁–C₆-alkyl heteroaryl”, “C₂–C₆-alkenyl aryl”, “C₂–C₆-alkenylheteroaryl”, “C₂–C₆-alkynyl aryl”, “C₂–C₆-alkynylheteroaryl”,“C₁–C₆-alkyl cycloalkyl”, “C₁–C₆-alkyl heterocycloalkyl”.

“C₁–C₆-alkyl acyl” refers to C₁–C₆-alkyl groups having an acylsubstituent, including 2-acetylethyl and the like.

“Aryl acyl” refers to aryl groups having an acyl substituent, including2-acetylphenyl and the like.

“Heteroaryl acyl” refers to hetereoaryl groups having an acylsubstituent, including 2-acetylpyridyl and the like.

“C₃–C₈-(hetero)cycloalkyl acyl” refers to 3 to 8 memebered cycloalkyl orheterocycloalkyl groups having an acyl substituent.

“Acyloxy” refers to the group —OC(O)R where R includes H, “C₁–C₆-alkyl”,“C₂–C₆-alkenyl”, “C₂–C₆-alkynyl”, “C₃–C₈-cycloalkyl”,heterocycloalkyl“heterocycloalkyl”, “aryl”, “heteroaryl”, “C₁–C₆-alkylaryl” or “C₁–C₆-alkyl heteroaryl”, “C₂–C₆-alkenyl aryl”, “C₂–C₆-alkenylheteroaryl”, “C₂–C₆-alkynyl aryl”, “C₂–C₆-alkynylheteroaryl”,“C₁–C₆-alkyl cycloalkyl”, “C₁–C₆-alkyl heterocycloalkyl”.

“C₁–C₆-alkyl acyloxy” refers to C₁–C₆-alkyl groups having an acyloxysubstituent, including 2-(acetyloxy)ethyl and the like.

“Alkoxy” refers to the group —O—R where R includes “C₁–C₆-alkyl”,“C₂–C₆-alkenyl”, “C₂–C₆-alkynyl”, “C₃–C₈-cycloalkyl”,“heterocycloalkyl”, “aryl”, “heteroaryl”, “C₁–C₆-alkyl aryl” or“C₁–C₆-alkyl heteroaryl”, “C₂–C₆-alkenyl aryl”, “C₂–C₆-alkenylheteroaryl”, “C₂–C₆-alkynyl aryl”, “C₂–C₆-alkynylheteroaryl”,“C₁–C₆-alkyl cycloalkyl”, “C₁–C₆-alkyl heterocycloalkyl”.

“C₁–C₆-alkyl alkoxy” refers to C₁–C₆-alkyl groups having an alkoxysubstituent, including 2-ethoxyethyl and the like.

“Alkoxycarbonyl” refers to the group —C(O)OR where R includes“C₁–C₆-alkyl”, “C₂–C₆-alkenyl”, “C₂–C₆-alkynyl”, “C₃–C₈-cycloalkyl”,“heterocycloalkyl”, “aryl”, “heteroaryl”, “C₁–C₆-alkyl aryl” or“C₁–C₆-alkyl heteroaryl”, “C₂–C₆-alkenyl aryl”, “C₂–C₆-alkenylheteroaryl”, “C₂–C₆-alkynyl aryl”, “C₂–C₆-alkynylheteroaryl”,“C₁–C₆-alkyl cycloalkyl”, “C₁–C₆-alkyl heterocycloalkyl”.

“C₁–C₆-alkyl alkoxycarbonyl” refers to C₁–C₆-alkyl groups having analkoxycarbonyl substituent, including 2-(benzyloxycarbonyl)ethyl and thelike.

“Aminocarbonyl” refers to the group —C(O)NRR′ where each R, R′ includesindependently hydrogen, “C₁–C₆-alkyl”, “C₂–C₆-alkenyl”, “C₂–C₆-alkynyl”,“C₃–C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁–C₆-alkyl aryl” or “C₁–C₆-alkyl heteroaryl”, “C₂–C₆-alkenyl aryl”,“C₂–C₆-alkenyl heteroaryl”, “C₂–C₆-alkynyl aryl”,“C₂–C₆-alkynylheteroaryl”, “C₁–C₆-alkyl cycloalkyl”, “C₁–C₆-alkylheterocycloalkyl”.

“C₁–C₆-alkyl aminocarbonyl” refers to C₁–C₆-alkyl groups having anaminocarbonyl substituent, including 2-(dimethylaminocarbonyl)ethyl andthe like.

“Acylamino” refers to the group —NRC(O)R′ where each R, R′ isindependently hydrogen, “C₁–C₆-alkyl”, “C₂–C₆-alkenyl”, “C₂–C₆-alkynyl”,“C₃–C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁–C₆-alkyl aryl” or “C₁–C₆-alkyl heteroaryl”, “C₂–C₆-alkenyl aryl”,“C₂–C₆-alkenyl heteroaryl”, “C₂–C₆-alkynyl aryl”,“C₂–C₆-alkynylheteroaryl”, “C₁–C₆-alkyl cycloalkyl”, “C₁–C₆-alkylheterocycloalkyl”.

“C₁–C₆-alkyl acylamino” refers to C₁–C₆-alkyl groups having an acylaminosubstituent, including 2-(propionylamino)ethyl and the like.

“Ureido” refers to the group —NRC(O)NR′R″ where each R, R′, R″ isindependently hydrogen, “C₁–C₆-alkyl”, “C₂–C₆-alkenyl”, “C₂–C₆-alkynyl”,“C₃–C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁–C₆-alkyl aryl” or “C₁–C₆-alkyl heteroaryl”, “C₂–C₆-alkenyl aryl”,“C₂–C₆-alkenyl heteroaryl”, “C₂–C₆-alkynyl aryl”,“C₂–C₆-alkynylheteroaryl”, “C₁–C₆-alkyl cycloalkyl”, “C₁–C₆-alkylheterocycloalkyl”, and where R′ and R″, together with the nitrogen atomto which they are attached, can optionally form a 3–8-memberedheterocycloalkyl ring.

“C₁–C₆-alkyl ureido” refers to C₁–C₆-alkyl groups having an ureidosubstituent, including 2-(N′-methylureido)ethyl and the like.

“Carbamate” refers to the group —NRC(O)OR′ where each R, R′ isindependently hydrogen, “C₁–C₆-alkyl”, “C₂–C₆-alkenyl”, “C₂–C₆-alkynyl”,“C₃–C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁–C₆-alkyl aryl” or “C₁–C₆-alkyl heteroaryl”, “C₂–C₆-alkenyl aryl”,“C₂–C₆-alkenyl heteroaryl”, “C₂–C₆-alkynyl aryl”,“C₂–C₆-alkynylheteroaryl”, “C₁–C₆-alkyl cycloalkyl”, “C₁–C₆-alkylheterocycloalkyl”.

“Amino” refers to the group —NRR′ where each R, R′ is independentlyhydrogen, “C₁–C₆-alkyl”, “C₂–C₆-alkenyl”, “C₂–C₆-alkynyl”,“C₃–C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁–C₆-alkyl aryl” or “C₁–C₆-alkyl heteroaryl”, “C₂–C₆-alkenyl aryl”,“C₂–C₆-alkenyl heteroaryl”, “C₂–C₆-alkynyl aryl”,“C₂–C₆-alkynylheteroaryl”, “C₁–C₆-alkyl cycloalkyl”, “C₁–C₆-alkylheterocycloalkyl”, and where R and R′, together with the nitrogen atomto which they are attached, can optionally form a 3–8-memberedheterocycloalkyl ring.

“C₁–C₆-alkyl amino” refers to C₁–C₆-alkyl groups having an aminosubstituent, including 2-(1-pyrrolidinyl)ethyl and the like.

“Ammonium” refers to a positively charged group —N⁺RR′R″, where each R,R′, R″ is independently, “C₁–C₆-alkyl”, “C₂–C₆-alkenyl”,“C₂–C₆-alkynyl”, “C₃–C₈-cycloalkyl”, “heterocycloalkyl”, “C₁–C₆-alkylaryl” or “C₁–C₆-alkyl heteroaryl”, “C₂–C₆-alkenyl aryl”, “C₂–C₆-alkenylheteroaryl”, “C₂–C₆-alkynyl aryl”, “C₂–C₆-alkynylheteroaryl”,“C₁–C₆-alkyl cycloalkyl”, “C₁–C₆-alkyl heterocycloalkyl”, and where Rand R′, together with the nitrogen atom to which they are attached, canoptionally form a 3–8-membered heterocycloalkyl ring.

“C₁–C₆-alkyl ammonium” refers to C₁–C₆-alkyl groups having an ammoniumsubstituent, including 2-(1-pyrrolidinyl)ethyl and the like.

“Ionisable moiety” refers to a moiety which may be transformed into asalt, e.g. by protonation Amino or sulfonyl moieties are examples forionisable/protonable moities.

“Halogen” refers to fluoro, chloro, bromo and iodo atoms.

“Sulfonyloxy” refers to a group —OSO₂—R wherein R is selected from H,“C₁–C₆-alkyl”, “C₁–C₆-alkyl” substituted with halogens, e.g., an—OSO₂—CF₃ ⁻ group, “C₂–C₆-alkenyl”, “C₂–C₆-alkynyl”, “C₃–C₈-cycloalkyl”,“heterocycloalkyl”, “aryl”, “heteroaryl”, “C₁–C₆-alkyl aryl” or“C₁–C₆-alkyl heteroaryl”, “C₂–C₆-alkenyl aryl”, “C₂–C₆-alkenylheteroaryl”, “C₂–C₆-alkynyl aryl”, “C₂–C₆-alkynylheteroaryl”,“C₁–C₆-alkyl cycloalkyl”, “C₁–C₆-alkyl heterocycloalkyl”.

“C₁–C₆-alkyl sulfonyloxy” refers to C₁–C₆-alkyl groups having asulfonyloxy substituent, including 2-(methylsulfonyloxy)ethyl and thelike.

“Sulfonyl” refers to group “—SO₂—R” wherein R is selected from H,“aryl”, “heteroaryl”, “C₁–C₆-alkyl”, “C₁–C₆-alkyl” substituted withhalogens, e.g., an —SO₂—CF₃ group, “C₂–C₆-alkenyl”, “C₂–C₆-alkynyl”,“C₃–C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁–C₆-alkyl aryl” or “C₁–C₆-alkyl heteroaryl”, “C₂–C₆-alkenyl aryl”,“C₂–C₆-alkenyl heteroaryl”, “C₂–C₆-alkynyl aryl”,“C₂–C₆-alkynylheteroaryl”, “C₁–C₆-alkyl cycloalkyl”, “C₁–C₆-alkylheterocycloalkyl”.

“C₁–C₆-alkyl sulfonyl” refers to C₁–C₆-alkyl groups having a sulfonylsubstituent, including 2-(methylsulfonyl)ethyl and the like.

“Sulfinyl” refers to a group “—S(O)—R” wherein R is selected from H,“C₁–C₆-alkyl”, “C₁–C₆-alkyl” substituted with halogens, e.g., an —SO—CF₃group, “C₂–C₆-alkenyl”, “C₂–C₆-alkynyl”, “C₃–C₈-cycloalkyl”,“heterocycloalkyl”, “aryl”, “heteroaryl”, “C₁–C₆-alkyl aryl” or“C₁–C₆-alkyl heteroaryl”, “C₂–C₆-alkenyl aryl”, “C₂–C₆-alkenylheteroaryl”, “C₂–C₆-alkynyl aryl”, “C₂–C₆-alkynylheteroaryl”,“C₁–C₆-alkyl cycloalkyl”, “C₁–C₆-alkyl heterocycloalkyl”.

“C₁–C₆-alkyl sulfinyl” refers to C₁–C₆-alkyl groups having a sulfinylsubstituent, including 2-(methylsulfinyl)ethyl and the like.

“Sulfanyl” refers to groups —S—R where R includes H, “C₁–C₆-alkyl”,“C₁–C₆-alkyl” substituted with halogens, e.g., an —SO—CF₃ group,“C₂–C₆-alkenyl”, “C₂–C₆-alkynyl”, “C₃–C₈-cycloalkyl”,“heterocycloalkyl”, “aryl”, “heteroaryl”, “C₁–C₆-alkyl aryl” or“C₁–C₆-alkyl heteroaryl”, “C₂–C₆-alkenyl aryl”, “C₂–C₆-alkenylheteroaryl”, “C₂–C₆-alkynyl aryl”, “C₂–C₆-alkynylheteroaryl”,“C₁–C₆-alkyl cycloalkyl”, “C₁–C₆-alkyl heterocycloalkyl”. Preferredsulfanyl groups include methylsulfanyl, ethylsulfanyl, and the like.

“C₁–C₆-alkyl sulfanyl” refers to C₁–C₆-alkyl groups having a sulfanylsubstituent, including 2-(ethylsulfanyl)ethyl and the like.

“Sulfonylamino” refers to a group —NRSO₂—R′ where each R, R′ includesindependently hydrogen, “C₁–C₆-alkyl”, “C₂–C₆-alkenyl”, “C₂–C₆-alkynyl”,“C₃–C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁–C₆-alkyl aryl” or “C₁–C₆-alkyl heteroaryl”, “C₂–C₆-alkenyl aryl”,“C₂–C₆-alkenyl heteroaryl”, “C₂–C₆-alkynyl aryl”,“C₂–C₆-alkynylheteroaryl”, “C₁–C₆-alkyl cycloalkyl”, “C₁–C₆-alkylheterocycloalkyl”.

“C₁–C₆-alkyl sulfonylamino” refers to C₁–C₆-alkyl groups having asulfonylamino substituent, including 2-(ethylsulfonylamino)ethyl and thelike.

“Aminosulfonyl” refers to a group —SO₂—NRR′ where each R, R′ includesindependently hydrogen, “C₁–C₆-alkyl”, “C₂–C₆-alkenyl”, “C₂–C₆-alkynyl”,“C₃–C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁–C₆-alkyl aryl” or “C₁–C₆-alkyl heteroaryl”, “C₂–C₆-alkenyl aryl”,“C₂–C₆-alkenyl heteroaryl”, “C₂–C₆-alkynyl aryl”,“C₂–C₆-alkynylheteroaryl”, “C₁–C₆-alkyl cycloalkyl”, “C₁–C₆-alkylheterocycloalkyl”.

“C₁–C₆-alkyl aminosulfonyl” refers to C₁–C₆-alkyl groups having anaminosulfonyl substituent, including 2-(cyclohexylaminosulfonyl)ethyland the like.

“Substituted or unsubstituted”: Unless otherwise constrained by thedefinition of the individual substituent, the above set out groups, like“alkyl”, “alkenyl”, “alkynyl”, “aryl” and “heteroaryl” etc. groups canoptionally be substituted with from 1 to 5 substituents selected fromthe group consisting of “C₁–C₆-alkyl”, “C₂–C₆-alkenyl”, “C₂–C₆-alkynyl”,“cycloalkyl”, “heterocycloalkyl”, “C₁–C₆-alkyl aryl”, “C₁–C₆-alkylheteroaryl”, “C₁–C₆-alkyl cycloalkyl”, “C₁–C₆-alkyl heterocycloalkyl”,“amino”, “ammonium”, “acyl”, “acyloxy”, “acylamino”, “aminocarbonyl”,“alkoxycarbonyl”, “ureido”, “carbamate”, “aryl”, “heteroaryl”,“sulfinyl”, “sulfonyl”, “alkoxy”, “sulfanyl”, “halogen”, “carboxy”,trihalomethyl, cyano, hydroxy, mercapto, nitro, and the like.Alternatively said substitution could also comprise situations whereneighbouring substituents have undergone ring closure, notably whenvicinal functional substituents are involved, thus forming, e.g.,lactams, lactons, cyclic anhydrides, but also acetals, thioacetals,aminals formed by ring closure for instance in an effort to obtain aprotective group.

“Pharmaceutically acceptable salts or complexes” refers to salts orcomplexes of the below-identified compounds of formula that retain thedesired biological activity. Examples of such salts include, but are notrestricted to acid addition salts formed with inorganic acids (e.g.,hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid, and the like), and salts formed with organic acids such asacetic acid, oxalic acid, tartaric acid, succinic acid, malic acid,fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid,pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid,naphthalene disulfonic acid, methanesulfonic acid and poly-galacturonicacid. Said compounds can also be administered as pharmaceuticallyacceptable quaternary salts known by a person skilled in the art, whichspecifically include the quarternary ammonium salt of the formula—NR,R′,R″⁺Z⁻, wherein R, R′, R″ is independently hydrogen, alkyl, orbenzyl, C₁–C₆-alkyl, C₂–C₆-alkenyl, C₂–C₆-alkynyl, C₁–C₆-alkyl aryl,C₁–C₆-alkyl heteroaryl, cycloalkyl, heterocycloalkyl, and Z is acounterion, including chloride, bromide, iodide, —O-alkyl,toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate(such as benzoate, succinate, acetate, glycolate, maleate, malate,fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, anddiphenylacetate).

“Pharmaceutically active derivative” refers to any compound that uponadministration to the recipient, is capable of providing directly orindirectly, the activity disclosed herein.

“Enantiomeric excess” (ee) refers to the products that are obtained byan asymmetric synthesis, i.e. a synthesis involving non-racemic startingmaterials and/or reagents or a synthesis comprising at least oneenantioselective step, whereby a surplus of one enantiomer in the orderof at least about 52% ee is yielded. In the absence of an asymmetricsynthesis, racemic products are usually obtained that do however alsohave the inventive set out activity as OT-R antagonists.

General formula (I) of the present invention also comprises itstautomers, its geometrical isomers, its optically active forms asenantiomers, diastereomers and its racemate forms, as well aspharmaceutically acceptable salts thereof. Preferred pharmaceuticallyacceptable salts of the formula (I) are acid addition salts formed withpharmaceutically acceptable acids like hydrochloride, hydrobromide,sulfate or bisulfate, phosphate or hydrogen phosphate, acetate,benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate,gluconate, methanesulfonate, benzenesulfonate, and para-toluenesulfonatesalts.

One aspect of the present invention consists in the pyrrolidineoxadiazole and thiadiazole compounds of formula (I).

Pyrrolidine oxadiazole and thiadiazole derivatives according to formulaI are suitable to modulate, in particular to inhibit the OT-R functionand more specifically to antagonise the oxytocin receptor. When theoxytocin receptor is bound by the compounds according to formula I,oxytocin is antagonised by being blocked from its receptor and istherefore unable to exert its biologic or pharmacological effects. Thecompounds of the present invention are therefore in particular useful inthe treatment and/or prevention of oxytocin-related disorders of mammalsand in particular of humans.

The compounds according to the present invention are those of formula I.

Said formula also comprises its geometrical isomers, its opticallyactive forms as enantiomers, diastereomers and its racemate forms, aswell as pharmaceutically acceptable salts thereof. Preferredpharmaceutically acceptable salts of the compound I are acid additionsalts formed with pharmaceutically acceptable acids like hydrochloride,hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate,acetate, benzoate, succinate, fumarate, maleate, lactate, citrate,tartrate, gluconate, methanesulfonate (mesylate), benzenesulfonate, andpara-toluenesulfonate salts.

In said formula (I), A is selected from the group consisting of —(C═O)—,—(C═O)—O—, —SO₂—, —SO₂NH—, —C(═NH)—, —(C═O)—NH—, —(C═S)—NH, —CH₂—. Mostpreferred is A being a carbonyl group.

B is an unsubstituted or substituted oxadiazole or thiadiazole ring.

R¹ is selected from the group comprising or consisting of unsubstitutedor substituted C₁–C₆-alkyl, unsubstituted or substituted C₂–C₆-alkenyl,unsubstituted or substituted C₂–C₆-alkynyl, unsubstituted or substitutedaryl, unsubstituted or substituted heteroaryl, unsubstituted orsubstituted C₁–C₆-alkyl aryl, unsubstituted or substituted C₁–C₆-alkylheteroaryl, R¹ can form with the O atom to which it is attached a 3–8membered substituted or unsubstituted, saturated or unsaturatedheterocyclic ring which may contain 1–2 further heteroatoms selectedfrom N, S and O and which is optionally fused with an aryl, heteroarylor 3–8 membered saturated or unsaturated cycloalkyl ring. Preferably, R¹is H or a C₁–C₃-alkyl, most preferred a methyl group.

R² is selected from the group comprising or consisting of unsubstitutedor substituted C₁–C₆-alkyl, unsubstituted or substituted C₂–C₆-alkenyl,unsubstituted or substituted C₂–C₆-alkynyl, unsubstituted or substitutedaryl, unsubstituted or substituted heteroaryl, unsubstituted orsubstituted saturated or unsaturated 3–8-membered cycloalkyl, acyl,unsubstituted or substituted C₁–C₆-alkyl aryl, unsubstituted orsubstituted C₁–C₆-alkyl heteroaryl, said cycloalkyl or aryl orheteroaryl groups may be fused with 1–2 further cycloalkyl or aryl orheteroaryl group. More a preferred is an aryl, in particular a phenylgroup which is optionally substituted, e.g. by a further phenyl group(thus providing a biphenyl moiety).

R³, R⁴, R⁵ and R⁶ are independently selected from each other from thegroup consisting of hydrogen, halogen, C₁–C₆-alkyl, C₁–C₆-alkoxy.Preferably each of them is H.

Preferred pyrrolidine derivatives are those compounds according toformula I wherein R¹ is selected from the group consisting of H or—C₁–C₆ alkyl, in particular —CH₃, A is —(C═O)—, R² is a substituted orunsubstituted aryl, a substituted or unsubstituted heteroaryl group,particularly a biphenyl group.

According to a preferred embodiment, the substituent B is a 1,2,4oxadiazole substituent which may be attached to the pyrrolidine ringaccording to the following modes (IIa) or (IIb):

In said formulae (IIa) and (IIb), R₇ is selected from the groupcomprising or consisting of hydrogen, sulfonyl, amino, unsubstituted orsubstituted C₁–C₆-alkyl, unsubstituted or substituted C₂–C₆-alkenyl,unsubstituted or substituted C₂–C₆-alkynyl, wherein said alkyl, alkenyl,alkynyl chains may be interrupted by a heteroatom selected from N, O orS, unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted saturated or unsaturated3–8-membered cycloalkyl, unsubstituted or substituted heterocycloalkyl,wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups maybe fused with 1–2 further cycloalkyl, heterocycloalkyl, aryl orheteroaryl group, an acyl moiety, unsubstituted or substitutedC₁–C₆-alkyl aryl, unsubstituted or substituted C₁–C₆-alkyl heteroaryl,unsubstituted or substituted C₁–C₆-alkenyl aryl, unsubstituted orsubstituted C₁–C₆-alkenyl heteroaryl, unsubstituted or substitutedC₁–C₆-alkynyl aryl, unsubstituted or substituted C₁–C₆-alkynylheteroaryl, unsubstituted or substituted C₁–C₆-alkyl cycloalkyl,unsubstituted or substituted C₁–C₆-alkyl heterocycloalkyl, unsubstitutedor substituted C₁–C₆-alkenyl cycloalkyl, unsubstituted or substitutedC₁–C₆-alkenyl heterocycloalkyl, unsubstituted or substitutedC₁–C₆-alkynyl cycloalkyl, unsubstituted or substituted C₁–C₆-alkynylheterocycloalkyl, substituted or unsubstituted alkoxycarbonyl,substituted or unsubstituted aminocarbonyl, substituted or unsubstitutedC₁–C₆-alkyl carboxy, substituted or unsubstituted C₁–C₆-alkyl acyl,substituted or unsubstituted aryl acyl, substituted or unsubstitutedheteroaryl acyl, substituted or unsubstituted C₃–C₈-(hetero)cycloalkylacyl, unsubstituted or substituted C₁–C₆-alkyl acyloxy, unsubstituted orsubstituted C₁–C₆-alkyl alkoxy, unsubstituted or substituted C₁–C₆-alkylalkoxycarbonyl, unsubstituted or substituted C₁–C₆-alkyl aminocarbonyl,unsubstituted or substituted C₁–C₆-alkyl acylamino, acylamino,unsubstituted or substituted C₁–C₆-alkyl ureido, substituted orunsubstituted C₁–C₆-alkyl carbamate, unsubstituted or substitutedC₁–C₆-alkyl amino, unsubstituted or substituted C₁–C₆-alkyl ammonium,unsubstituted or substituted C₁–C₆-alkyl sulfonyloxy, unsubstituted orsubstituted C₁–C₆-alkyl sulfonyl, unsubstituted or substitutedC₁–C₆-alkyl sulfinyl, unsubstituted or substituted C₁–C₆-alkyl sulfanyl,unsubstituted or substituted C₁–C₆-alkyl sulfonylamino, unsubstituted orsubstituted C₁–C₆-alkyl aminosulfonyl, hydroxy, halogen, cyano.

According to a preferred embodiment, R⁷ is a substituent comprising anionisable (notably a protonable) moiety.

Specifically, R⁷ may be selected from the group consisting of a carboxyor an amino moiety.

Alternatively, R⁷ may be selected from the group consisting of from anyof the above mentioned substituents which carries at least one carboxyor an amino moiety. A preferred ionisable (protonable) moiety is acyclic tertiary amine (being a hetereocycloalkyl).

More preferred are C₁–C₆-alkyl amino, heterocycloalkyl like piperazinesor piperidines, C₁–C₆-alkyl heterocycloalkyl, aminocarbonyl, C₁–C₆-alkylaminocarbonyl, C₁–C₆-alkyl acylamino, C₁–C₆-alkyl sulfonyl, C₁–C₆-alkylcarboxy. Most preferred are dimethylaminomethyl, 2-(dimethylamino)ethyl,1-methyl-3-piperidinyl, (4-acetyl-1-piperazinyl)methyl.

According to another embodiment, the substituent B is a 1,3,4-oxadiazoleof formula (IV) or its tautomer of formula (III):

X in said formulae (III) and (IV) is O or S, whereby in case the case offormula IV, X may also be a bond. In the case where X is O or S, and R₈is hydrogen, compounds of formula IV represent the correspondingtautomers of formula III.

R₈ of formula (IV) is selected from the group comprising or consistingof hydrogen unsubstituted or substituted C₁–C₆-alkyl, unsubstituted orsubstituted C₂–C₆-alkenyl, unsubstituted or substituted C₂–C₆-alkynyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted saturated or unsaturated3–8-membered cycloalkyl, optionally containing at least one heteroatom(e.g. 1 to 3) selected from N, O, S, an acyl moiety, unsubstituted orsubstituted C₁–C₆-alkyl aryl, unsubstituted or substituted C₁–C₆-alkylheteroaryl, unsubstituted or substituted C₁–C₆-alkenyl aryl,unsubstituted or substituted C₁–C₆-alkenyl heteroaryl, substituted orunsubstituted alkoxycarbonyl, carboxylic amide, substituted orunsubstituted C₁–C₆-alkoxy, substituted or unsubstituted aryloxy,substituted or unsubstituted heteroaryloxy, halogen, cyano, substitutedor unsubstituted C₁–C₆-alkyl carbonyl, substituted or unsubstitutedarylcarbonyl or heteroarylcarbonyl, substituted or unsubstitutedsaturated or unsaturated C₄–C₈-cycloalkylcarbonyl, wherein saidcycloalkyl or aryl or heteroaryl groups may be fused with 1–2 furthercycloalkyl or aryl or heteroaryl group and wherein said alkyl, alkenyl,alkynyl chain may be interrupted by an heteroatom selected from N, O orS

Particularly more preferred pyrrolidine derivatives are those compoundsaccording to formula I wherein A is —(C═O), R¹ is a C₁–C₆ alkyl group,R² is either a aryl group or a heteroaryl, each of R³, R⁴, R⁵ and R⁶ isH and B is an oxadiazole according to formulae IIa, IIb, III or IV.

Most preferred pyrrolidine derivatives are those compounds according toformula I, wherein A is —(C═O), R¹ is a methyl group, R² is either an(un)substituted aryl group or an (un)substituted heteroaryl, each of R³,R⁴, R⁵ and R⁶ is H and B is an oxadiazole according to formulae IIa,IIb, III and IV, particularly a 1,2,4 oxadiazole of formulae IIa or IIb.

Most preferred pyrrolidine derivatives are those compounds according toformula I wherein A is —(C═O), R¹ is a methyl group, R² is a biphenylgroup, each of R³, R⁴, R⁵ and R⁶ is H and B is an oxadiazole accordingto formulae IIa, IIb, III and IV, particularly a 1,2,4 oxadiazole offormula IIa or IIb.

The compounds of formula I may contain one or more asymmetric centersand may therefore exist as enantiomers or diasteroisomers. It is to beunderstood that the invention includes both mixtures and separateindividual isomers or enantiomers of the compounds of formula I. In aparticularly preferred embodiment the pyrrolidine derivatives accordingto formula I are obtained in an enantiomeric excess of at least 52% ee,preferably of at least 92–98% ee.

Specific examples of compounds of formula I include the following:

-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(1,3,4-oxadiazol-2-yl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-oxo-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-5-(3-benzyl-1,2,4-oxadiazol-5-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(3-{[(2-furylmethyl)sulfanyl]methyl}-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(2-pyridinylsulfanyl)methyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(2-thienylsulfanyl)methyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(methylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(5-methyl-3-isoxazolyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-thienylmethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(3-phenyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(3-{[(2-furylmethyl)sulfonyl]methyl}-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-5-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(RS)-hydroxy(phenyl)methyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(1RS)-1-hydroxypropyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-hydroxymethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(1S,2R)-2-hydroxycyclohexyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone    O-methyloxime-   (3Z,5RS)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(3RS)-piperidinyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(2RS)-piperidinyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-[(2′-chloro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-1-{[2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-3-pyrrolidinone    O-methyloxime-   (3Z,5S)-1-[(2′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-[(4′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(1,2,4-oxadiazol-3-yl)-3-pyrrolidinone    O-methyloxime-   (3E,5S)-1-[(2′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone    O-methyloxime-   (3E,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone    O-methyloxime-   (3Z,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(phenoxymethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-phenyl-1,2,4-oxadiazol-3-yl)-3-pyrrolidinone    O-methyloxime-   N-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)acetamide-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[4-(hydroxymethyl)phenyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(2-hydroxyethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(2S)-2-hydroxy-2-phenylethyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone    O-methyloxime-   {3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methylformamide-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(methoxymethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(2-phenoxyethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(2-methoxyethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-5-[5-(1-acetyl-4-piperidinyl)-1,2,4-oxadiazol-3-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(3-thienyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-cyclopentyl-1,2,4-oxadiazol-3-yl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(RS)-hydroxy(phenyl)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(1RS)-1-hydroxy-2-phenylethyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(1R)-1-(dimethylamino)-2-phenylethyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone    O-methyloxime.-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(3-pyridinyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(4-pyridinyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone    O-methyloxime-   (3Z,5S)-5-{5-[(4-acetyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-5-[3-(1-acetyl-4-piperidinyl)-1,2,4-oxadiazol-5-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-5-{5-[(4-acetyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone    O-methyloxime-   N-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-3-(1-piperidinyl)propanamide-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(3)-1-methylpiperidinyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(3R)-1-methylpiperidinyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(6-hydroxy-3-pyridinyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone    O-methyloxime-   (3Z,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(dimethylamino)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-5-{5-[(1S,2R)-1-amino-2-hydroxypropyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(3S)-piperidinyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(3R)-piperidinyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5RS)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(1-methyl-3-piperidinyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone    O-methyloxime-   tert-butyl    (3R)-3-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}-1-piperidinecarboxylate-   4-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-2,6-piperazinedione-   (3Z,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone    O-methyloxime-   (3Z,5S)-1-[(2′-chloro-4′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(1-methyl-4-piperidinyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(dimethylamino)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(1-methyl-4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-5-{5-[(1S)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone    O-methyloxime-   5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-N-[3-(dimethylamino)propyl]-1,2,4-oxadiazole-3-carboxamide-   (3E,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(dimethylamino)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone    O-methyloxime-   tert-butyl    (3S)-3-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl)}-1-piperidinecarboxylate-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(4-methyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone    O-methyloxime-   (3Z,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(4-methyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone    O-methyloxime-   ethyl    5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazole-3-carboxylate-   (3E,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone    O-methyloxime-   N-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-3-(dimethylamino)propanamide-   tert-butyl    4-(2-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}ethyl)-1-piperazinecarboxylate-   (3EZ,5S)-1-[(2′-chloro-4′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-[(4′-fluoro-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[2-(dimethylamino)ethyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone    O-methyloxime-   2-{5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-3-yl}ethyl[(tert-butoxycarbonyl)amino]acetate-   N-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-2-(dimethylamino)acetamide-   (3EZ,5S)-1-[(2′-chloro-4′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-5-{5-[(1S)-1-amino-2-tert-butoxyethyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone    O-methyloxime-   tert-butyl    4-{5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-3-yl)}-1-piperidinecarboxylate-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(1-piperazinylmethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone    O-methyloxime-   tert-butyl(4S)-4-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}-4-[(tert-butoxycarbonyl)amino]butanoate-   4-{[(2S,4EZ)-2-(5-{([(tert-butoxycarbonyl)amino]methyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl-   tert-butyl    2-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}ethylcarbamate-   2-{5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-3-yl}ethyl    aminoacetate-   (3E,5S)-1-[(2′,4′-difluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-[(2′,4′-difluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone    O-methyloxime-   4-{[(2S,4EZ)-2-(5-{(1S)-2-tert-butoxy-1-[(tert-butoxycarbonyl)amino]ethyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-vinyl-1,2,4-oxadiazol-3-yl)-3-pyrrolidinone    O-methyloxime-   4-{[(2S,4EZ)-2-(5-{(1S,2R)-2-tert-butoxy-1-[(tert-butoxycarbonyl)amino]propyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl-   (3Z,5S)-1-[(2′,4′-difluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone    O-methyloxime-   tert-butyl    4-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-1-piperazinecarboxylate

A further aspect of the present invention is related to the use of thepyrrolidine oxadiazole or thiadiazole derivatives according to formula Ias a medicament in particular for the treatment and/or prevention ofpreterm labor, premature birth, for stopping labor prior to cesareandelivery and dysmenorrhea. Preferably, the compounds according toformula I are suitable for the modulation of the OT function, thusspecifically allowing the treatment and/or prevention of disorders whichare mediated by the oxytocin receptor. Said treatment involves themodulation—notably the down regulation or the antagonisation—of theoxytocin receptor.

More specifically, the compounds of the present invention are useful forthe treatment of preterm labor, dysmenorrhea and for stopping laborprior to cesarean delivery.

Still a further object of the present invention is a process forpreparing the pyrrolidine derivatives according to formula I.

The pyrrolidine derivatives exemplified in this invention can beprepared from readily available starting materials using the followinggeneral methods and procedures. It will be appreciated that wheretypical or preferred experimental conditions (i.e. reactiontemperatures, time, moles of reagents, solvents, etc.) are given, otherexperimental conditions can also be used unless otherwise stated.Optimum reaction conditions may vary with the particular reactants orsolvents used, but such conditions can be determined by one skilled inthe art by routine optimisation procedures.

Generally, the pyrrolidine derivatives according to the general formulaI could be obtained by several processes, using both solution-phase andsolid-phase chemistry protocols.

According to one process, pyrrolidine derivatives according to thegeneral formula I, whereby the substituent B is a 1,2,4 oxadiazole offormula (IIa), are prepared from the corresponding carboxylic acidcompounds V and amidoximes VI, whereby the substituents R¹–R⁷, and A,are as above defined, by well known solution-phase chemistry protocols,such as those described in the Examples and shown in Scheme 1, below.

The amidoxime components VI are either obtained from commercial sourcesor made from the corresponding nitrites VII, by treatment of the latterwith hydroxylamine under standard conditions well known to the personskilled in the art, such as those described in the Examples and shown inScheme 2 below.

The nitrile components VII are either obtained from commercial sourcesor made from, e.g. the corresponding carboxylic acids VIII, as shown inScheme 3, by any of the functional group interconversion methods wellknown to the person skilled in the art, used to transform a carboxylicacid into the corresponding nitrile. Examples include (i) the reductionof the carboxylic acid VIII into the corresponding carbaldehyde,followed by transformation to the corresponding oxime, and dehydratationof the latter to the corresponding nitrile VII using, e.g.N,N′-carbonyldiimidazole or similar reagents, or (ii) the transformationof the carboxylic acid VIII into the corresponding primary carboxamide,followed by dehydratation to the corresponding nitrile VII, usingstandard conditions well known to the person skilled in the art, such asthose described hereinafter in the Examples.

The pyrrolidine-2-carboxylic acids V (see Scheme 1), whereby thesubstituents R¹–R⁷, and A, are as above defined, can be prepared fromcompounds of general formula IX by reaction with substitutedhydroxylamines X using standard synthetic techniques as hereinafterdescribed in the Examples and shown in Scheme 4.

Compounds of formula X are either obtained from commercial sources orprepared from N-Boc-hydroxylamine XI and alkylating agents XII (X=Cl,Br, I), by standard synthetic techniques, as shown in Scheme 5 anddescribed hereinafter in the Examples.

The keto compounds of general formula IX, wherein the substituentsR¹–R⁷, and A, are as above defined, can be prepared by oxidation ofcommercially available, suitably N-protected, 4-hydroxyproline XIII,using standard synthetic techniques as hereinafter described in theExamples and shown in Scheme 6. Alternatively, the compounds of generalformula IX can, themselves, be obtained from compounds of formula Vthrough transformation of the oximether into the ketone moiety, e.g.under mild hydrolysis conditions as described hereinafter in theExamples. If, in this scenario, the keto compounds IX are subsequentlyre-exposed to a different hydroxylamine component X*, such as shown inScheme 6, then the overall transformation V→IX→V* will correspond to aninterchange of R¹ within the oximether moiety of compounds of generalformula V. The analogous oximether interconversion is possible on thelevel of the final compounds of general formula I (I→XIV→I*), as shownas well in Scheme 6.

According to another process, pyrrolidine derivatives according to thegeneral formula I, whereby the substituent B is a 1,2,4 oxadiazole offormula (IIb), are prepared from the corresponding amidoxime acidcompounds XV, whereby the substituents R¹–R⁷, and A, are as abovedefined, and carboxylic acids VIII, by well known solution-phasechemistry protocols, such as those described in the Examples and shownin Scheme 7, below.

The amidoxime components XV are obtained from the corresponding nitritesXVI, whereby the substituents R¹–R⁷, and A, are as above defined, bytreatment of the latter with hydroxylamine under standard conditionswell known to the person skilled in the art, such as those described inthe Examples and shown in Scheme 8 below. The nitrile components XVI,themselves, are prepared from, e.g. the corresponding carboxylic acidsV, wherein the substituents R¹–R⁷, and A, are as above defined, by anyof the functional group interconversion methods well known to the personskilled in the art, used to transform, a carboxylic acid into thecorresponding nitrile. Examples include (i) the reduction of thecarboxylic acid V into the corresponding carbaldehyde, followed bytransformation to the corresponding oxime, and dehydratation of thelatter to the corresponding nitrile XVI using, e.g.N,N′-carbonyldiimidazole or similar reagents, or (ii) the transformationof the carboxylic acid V into the corresponding primary carboxamide,followed by dehydratation to the corresponding nitrile XVI, usingstandard conditions well known to the person skilled in the art, such asthose described hereinafter in the Examples.

Pyrrolidine derivatives according to the general formula I, wherein thesubstituent B is a 1,3,4 oxadiazole of formula III and/or IV, may beprepared from the corresponding hydrazide compounds XVII, whereby thesubstituents R¹–R⁷, and A, are as above defined, by solution-phasechemistry protocols well known to the practicioner skilled in the art,such as those described in the Examples and shown in Scheme 9, below.For example, compounds of formula I wherein substituent B is a 1,3,4oxadiazole of formula III may be obtained by treatment of XVII with CDIor CS₂, under basic conditions, to afford the corresponding productswherein X is O or S, respectively. Alternatively, the hydrazideintermediate XVII can be treated with TMOF, followed by P₂O₅ inrefluxing toluene, to afford compounds of formula I wherein B is IV.

The hydrazide compounds XVII are obtained, e.g., from the correspondingcarboxylic acids V, whereby the substituents R¹–R⁷, and A, are as abovedefined, via the corresponding methylesters XVIII, and subsequenttreatment of the latter with hydrazine, under standard conditions wellknown to the person skilled in the art, such as those described in theExamples and shown in Scheme 10 below.

Compounds of general formula I, whereby the substituents R¹–R⁸, and A,are as above defined, are thus accessible from precursors of generalformula V/XVIII (see Schemes 1, 7–10 above). Usually, said precursors offormula V/XVIII will initially carry a protecting group for the nitrogenatom of the pyrrolidine ring, such as Boc, Fmoc, or others, hence V′and/or XVIII′ (-A-R²=protecting group, PG), as shown in Scheme 11. Forthe synthesis of the final compounds I, the N-protecting groups of V′and/or XVIII′ is typically removed and replaced by a suitableN-substituent, such as, e.g., an acyl group, —C(O)—R² or a —SO₂—R²group, e.g. by treatment with an acylating agent or sulfonating agentXX. Further compounds of formula (XX) are carboxylating agents,sulfonating agents, sulfonamidating agents, imidating agents, amidatingagents, thioamidating agents, or an alkylating agents. The attachment ofthe desired moiety (-A-R²) at the pyrrolidine nitrogen atom may beperformd either after or before the formation of the oxadiazole, orthiadiazole ring, as shown in Scheme 11 (A or B, respectively), anddescribed hereinafter in the Examples. The most appropriate choice ofthe synthetic sequence protocole will depend on the nature of thesubstituents R¹–R⁸ (in particular of R⁷). Preferred acylating agents XXare acid chlorides (XXa), usually employed in conjunction with asuitable tertiary amine base, or a carboxylic acid (XXb), used inconjunction with a peptide coupling agent, e.g. DIC or EDC.

Compounds of formula I wherein A is —(C═O)—O—, —SO₂—, —SO₂NH—, —C(═NH)—,—(C═O)—NH, —(C═S)—NH, —CH₂— may be prepared by using a correspondinglyadapted carboxylating agents, sulfonating agents, sulfonamidatingagents, imidating agents, amidating agents, thioamidating agents, oralkylating agents, e.g. sulfonyl chlorides, isocyanates,isothiocyanates, chloroformates, substituted alkyl halides, or others toyield sulfonamide, urea, thiourea, carbamate, substituted alkylderivatives, or others respectively.

According to a further general process, compounds of formula I can beconverted to alternative compounds of formula I′, by suitableprotection/deprotection/functional group interconversion techniques,well known to the person skilled in the art, as shown in Scheme 12 anddescribed hereinafter in the Examples.

According to yet another process, pyrrolidine derivatives according tothe general formula I, are prepared by a novel solid-phase protocol, asoutlined in Scheme 13 and described hereinafter in the Examples. Forexample, for the solid-phase synthesis of compounds of general structureI with B=IIa, the N-Boc-protected pyrrolidine derivative V is reactedwith a resin carrying a linker prone to cleavage by nucleophiles, e.g.with Kaiser oxime resin, using standard carbodiimide-mediated couplingconditions well known to the practitioner skilled in the art.Boc-deprotection with dilute TFA in DCM, or with BF₃.OEt₂ in dilute HOAcin DCM, affords compounds of formula XXIV. The latter compound can betreated with acylating agents of general formula XX, whereby thesubstituents A and R² are as above defined, and LG could be anappropriate leaving group. Preferred acylating agents XX are acidchlorides (XXa), used in conjunction with a tertiary amine base, orcarboxylic acids (XXb), used in conjunction with a peptide couplingagent, such as e.g. DIC, EDC, TBTU, DECP, or others, to yield productsof general formula XXIII. Compounds of formula I wherein A is differentfrom the carbonyl functionality are prepared by replacing formula XXwith compounds containing the appropriate-functional groups, e.g.sulfonyl chlorides, isocyanates, isothiocyanates, chloroformates,substituted alkyl halides, or others to yield sulfonamide, urea,thiourea, carbamate, substituted alkyl derivatives, or othersrespectively. In order to obtain the final compounds of general formulaI, the linkage to the resin is cleaved by prolonged treatment withamidoximes VI, followed by heating with, e.g., pyridine. The circles inScheme 13 symbolize the resin beads to which the corresponding compoundsare linked during the solid phase synthesis. Other derivatives offormula I are prepared using known modifications to, or variations of,the Scheme 13 reaction sequence. Further to the abovementioned Kaiseroxime resin, other suitable reagents, notably resins, known to a personskilled in the art, could be employed for the solid-phase synthesis ofcompounds of general formula I.

The reaction sequences outlined in the above Schemes provideenantiomerically pure compounds of formula I, if enantiomerically purestarting materials are used. (R)- as well as (S)-enantiomers can beobtained depending upon whether (R)- or (S)-forms of commerciallyavailable compounds of formulas V–VIII, X, and/or XX were used as thestarting materials.

However, the reaction sequences outlined in the above Schemes usuallyprovide mixtures of (E)- and (Z)-isomers with respect to thesubstituents on the exocyclic double bond of the pyrrolidine ring. Inall cases studied, these (E)/(Z)-isomers could be separated by standardchromatography techniques well known to the person skilled in the art,such as by reversed phase high-pressure liquid chromatography (HPLC) orsilica gel flash chromatography (FC). Alternatively, either one of the(E)/(Z)-isomers could successively be enriched by selectivecrystallisation in appropriate solvents or solvent mixtures. Theassignment of the absolute configuration of the exocyclic double bondwas performed using NMR-techniques well described in the literature aswill be known to the practitioner skilled in the art (forconfigurational assignments of e.g. oxime functionalities, see e.g. E.Breitmaier, W. Voelter Carbon-13 NMR Spectroscopy, 3rd Ed, VCH, 1987, p.240). In order to increase the overall yields of the preferred isomer(usually the (Z)-isomer), the less preferred isomer (usually the(E)-isomer) could be recycled by deliberate re-isomerization in organicsolvents containing traces of acid, such as HCl, followed again by(E)/(Z)-separation through chromatography and/or crystallization, asillustrated in Scheme 14.

If the above set out general synthetic methods are not applicable forobtaining compounds according to formula I and/or necessaryintermediates for the synthesis of compounds of formula I, suitablemethods of preparation known by a person skilled on the art should beused. In general, the synthesis pathways for any individual compound offormula I will depend on the specific substitutents of each molecule andupon the ready availability of intermediates necessary; again suchfactors being appreciated by those of ordinary skill in the art. For allthe protection, deprotection methods, see Philip J. Kocienski, in“Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994 and,Theodora W. Greene and Peter G. M. Wuts in “Protective Groups in OrganicSynthesis”, Wiley-Interscience, 1991.

Compounds of this invention can be isolated in association with solventmolecules by crystallization from evaporation of an appropriate solvent.The pharmaceutically acceptable acid addition salts of the compounds offormula I, which contain a basic center, may be prepared in aconventional manner. For example, a solution of the free base may betreated with a suitable acid, either neat or in a suitable solution, andthe resulting salt isolated either by filtration or by evaporation undervacuum of the reaction solvent. Pharmaceutically acceptable baseaddition salts may be obtained in an analogous manner by treating asolution of compound of formula I with a suitable base. Both types ofsalt may be formed or interconverted using ion-exchange resintechniques.

A final aspect of the present invention is related to the use of thecompounds according to formula I for the treatment of preterm labor,premature birth, dysmenorrhea, preferably the compounds of formula (I)are suitable for the modulation of the Oxytocin receptor, the use ofsaid compounds for the preparation of pharmaceutical compositions forthe modulation of the oxytocin receptor as well as the formulationscontaining the active compounds according to formula I. Said modulationof the oxytocin receptor is viewed as a suitable approach for thetreatment of preterm labor, premature birth and dysmenorrhea. Hence,pharmaceutical compositions comprising a compound of formula I and apharmaceutically acceptable carrier, diluent or excipient therefore arealso within the scope of the present invention. A person skilled in theart is aware of a whole variety of such carrier, diluent or excipientcompounds suitable to formulate a pharmaceutical composition. Also, thepresent invention provides; compounds for use as a medicament.

The compounds of the invention, together with a conventionally employedadjuvant, carrier, diluent or excipient may be placed into the form ofpharmaceutical compositions and unit dosages thereof, and in such formmay be employed as solids, such as tablets or filled capsules, orliquids such as solutions, suspensions, emulsions, elixirs, or capsulesfilled with the same, all for oral use, or in the form of sterileinjectable solutions for parenteral (including subcutaneous use). Suchpharmaceutical compositions and unit dosage forms thereof may compriseingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

When employed as pharmaceuticals, the pyrrolidine derivatives of thisinvention are typically administered in the form of a pharmaceuticalcomposition. Such compositions can be prepared in a manner well known inthe pharmaceutical art and comprise at least one active compound.Generally, the compounds of this invention are administered in apharmaceutically effective amount. The amount of the compound actuallyadministered will typically be determined by a physician, in the lightof the relevant circumstances, including the condition to be treated,the chosen route of administration, the actual compound administered,the age, weight, and response of the individual patient, the severity ofthe patient's symptoms, and the like.

The pharmaceutical compositions of these inventions can be administeredby a variety of routes including oral, rectal, transdermal,subcutaneous, intravenous, intramuscular, and intranasal. Thecompositions for oral administration can take the form of bulk liquidsolutions or suspensions, or bulk powders. More commonly, however, thecompositions are presented in unit dosage forms to facilitate accuratedosing. The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient. Typical unit dosage forms includeprefilled, premeasured ampoules or syringes of the liquid compositionsor pills, tablets, capsules or the like in the case of solidcompositions. In such compositions, the pyrrolidine oxadiazole compoundis usually a minor component (from about 0.1 to about 50% by weight orpreferably from about 1 to about 40% by weight) with the remainder beingvarious vehicles or carriers and processing aids helpful for forming thedesired dosing form.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatine; an excipient such as starch or lactose, a desintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As above mentioned, the pyrrolidine derivatives of formula Iin such compositions is typically a minor component, frequently rangingbetween 0.05 to 10% by weight with the remainder being the injectablecarrier and the like.

The above described components for orally administered or injectablecompositions are merely representative. Further materials as well asprocessing techniques and the like are set out in Part 8 of Remington'sPharmaceutical Sciences, 17^(th) Edition, 1985, Marck PublishingCompany, Easton, Pa., which is incorporated herein be reference.

The compounds of this invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can also befound in the incorporated materials in Remington's PharmaceuticalSciences.

In the following the present invention shall be illustrated by means ofsome examples which are not construed to be viewed as limiting the scopeof the invention. The HPLC, NMR and MS data provided in the examplesdescribed below were obtained as followed. The following abbreviationsare hereinafter used in the accompanying examples: min (minute), hr(hour), g (gram), mmol (millimole), m.p. (melting point), eq(equivalents), mL (milliliter), μL (microliters), mL (milliliters), ACN(Acetonitrile), Boc (butoxycarbonyl), CDCl₃ (deuterated chloroform), CDI(carbonyldiimidazole), cHex (Cyclohexanes), DCM (Dichloromethane), DECP(Diethylcyanophos-phonate), DIC (Diisopropyl carbodiimide), DMAP(4-Dimethylaminopyridine) DMF (Dimethylformamide), DMSO(Dimethylsulfoxide), DMSO-d₆ (deuterated dimethylsulfoxide), EDC(1-(3-Dimethyl-amino-propyl)-3-ethylcarbodiimide), EtOAc (Ethylacetate), Et₂O (Diethyl ether), Fmoc (9-fluorenylmethoxycarbonyl), HOBt(1-Hydroxybenzotriazole), Kaiser oxime resin (4-Nitrobenzophenone oximeresin); K₂CO₃ (potassium carbonate), NaH (Sodium hydride), NaHCO₃(Sodium bicarbonate), nBuLi (n Butyllithium), TBTU(O-Benzotriazolyl-N,N,N′,N′-tetramethyluronium-tetrafluoroborate), TEA(Triethyl amine), TFA (Trifluoroacetic acid), THF (Tetrahydrofuran),TMOF (trimethylorthoformate), MgSO₄ (Magnesium sulfate), PetEther(Petroleum ether), rt (room temperature).

EXAMPLES

Intermediate 1:(2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (cf.Scheme 6, compound XIII)

Commercial(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid(30 g, 0.13 mol) was dissolved in acetone (500 ml). A mechanical stirrerwas placed in the flask and the solution stirred vigorously. A freshlymade solution of 8N chromic acid was prepared by dissolving chromiumtrioxide (66.7 g, 0.667 mol) in water (40 ml), adding concentratedsulphuric acid (53.3 ml) and adding enough water to bring the solutionvolume to 115 ml. The 8N chromic acid solution (115 ml) was then addeddropwise over a period of 30 minutes with continued vigorous stirring,the reaction's exotherm being maintained at the optimal temperature of25° C. by the use of an ice bath. After the complete addition of thechromic acid, the reaction mixture was stirred for a further 15minutes—maintaining the optimal temperature of 25° C. The reactionmixture was then quenched by the addition of methanol (20 ml). Exothermcontrolled by the use of an ice bath and, if necessary, direct additionof a small amount of crushed ice to the reaction mixture itself. Thereaction mixture was filtered through a Celite pad and then concentratedin vacuo. The resulting acidic solution was then extracted with ethylacetate (3×300 ml) and the combined organic layers washed with brine(2×100 ml). Organics then dried with magnesium sulfate and concentratedin vacuo. Crude product recrystallised from ethyl acetate to give thewhite crystalline product,(2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (22.55g, 76%). The antipodal intermediate,(2R)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid, wasmade according to the same protocol, starting from commercial(2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid.

1H NMR (360 MHz, CDCl3); 1.4 (m, 9H), 2.5–3.0 (m, 2H), 3.7–3.9 (m, 2H),4.75 (dd, 1H)

Intermediate 2:(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (cf. Scheme 4, compound V)

A solution was made containing(2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid(Intermediate 1, 5.0 g, 21 mmol) and O-methylhydroxylamine hydrochloride(2.7 g, 32.8 mmol) in chloroform (100 ml) containing triethylamine (5.5g, 55 mmol). The reaction mixture was then stirred at ambienttemperature overnight, prior to removal of solvent. The resultant crudereaction mixture was dissolved in ethyl acetate (150 ml) and washedrapidly with 1N HCl (40 ml). The acidic layer was then extracted withethyl acetate (3×20 ml) and the combined organic layers washed withbrine before drying over magnesiom sulfate, filtering and removal ofsolvent in vacuo. The desired product (5.3 g, 94%) was isolated as apale yellow oil.

¹H NMR (400 MHz, CDCl₃); 1.45 (m, 9H), 2.8–3.2 (m, 2H), 3.9 (s, 3H), 4.2(m, 2H), 4.5–4.7 (m, 1H).

Intermediate 3:(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid (cf. Scheme 4, compound V)

A solution was made containing(2S)-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid(Intermediate 1, 5.0 g, 22 mmol) and O-ethylhydroxylamine hydrochloride(6.4 g, 65.5 mmol) in a 1:1 mixture of pyridine and ethanol (100 ml).The reaction was heated to reflux for 2.5 h before cooling and removalof solvent. The residue was dissolved in ethyl acetate and washedrapidly with 1.3N HCl (40 ml). The acidic layer was then extracted withethyl acetate (3×20 ml) and the combined organic layers washed withbrine before drying over magnesiom sulfate, filtering and removal ofsolvent in vacuo. The desired product (5.5 g, 93%) was isolated as apale yellow oil.

¹H NMR (400 MHz, DMSO); 1.3 (t, 3H), 1.55 (m, 9H), 2.9–2.7 (m, 1H),3.4–3.1 (m, 1H), 4.1–4.3 (m, 4H), 4.6 (m, 1H), 12–13.5 (br, 1H).

Intermediate 4:(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid (cf. Scheme 4, compound V)

A solution was made containing(2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid(Intermediate 1, 5.0 g, 22 mmol) and O-allylhydroxylamine hydrochloridemonohydrate (7.2 g, 65.5 mmol) in a 1:1 mixture of pyridine and ethanol(100 ml). The reaction was heated to reflux for 2.5 h before cooling andremoval of solvent. The residue was dissolved in ethyl acetate andwashed rapidly with 1.3N HCl (40 ml). The acidic layer was thenextracted with ethyl acetate (3×20 ml) and the combined organic layerswashed with brine before drying over magnesium sulfate, filtering andremoval of solvent in vacuo. The desired product (5.9 g, 94%) wasisolated as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃); 1.5 (m, 9H), 2.8–3.2 (m, 2H), 4.2 (m, 2H),4.5–4.7 (m, 3H), 5.25 (m, 2H), 5.9 (m, 1H), 11.1 (broad S, 1H).

Intermediate 5:(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidine-carboxylicacid (cf. Scheme 4, compound V)

The same method as employed in the preparation of Intermediate 2, butstarting from (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylicacid (Intermediate 1) and 1-[(aminooxy)methyl]-4-methoxybenzene(intermediate 6), gave the title compound as a gum in a 85% yield.

¹H NMR (400 MHz, DMSO); 1.5 (m, 9H), 2.7–2.9 (m, 1H) 3.9 (s, 3H), 4.2(m, 3H), 4.6 (m, 1H), 5.15 (s, 2H), 7.1 (d, 2H), 7.45 (d, 2H).

Intermediate 6: 1-[(aminooxy)methyl]-4-methoxybenzene (cf. Scheme 5,compound X)

A solution was made of N-Boc-hydroxylamine (2.0 g, 17.1 mmol) in dry THF(60 ml). Sodium hydride (1.1 g of a 60% suspension in paraffin oil, 25.7mmol) was then added and the suspension stirred. A catalytic amount ofKI was then added to the reaction prior to the cautious addition of4-methoxybenzyl chloride (3.2 g, 20.4 mmol). The reaction was thenallowed to stir overnight before removal of solvent in vacuo. Theresidue was taken up with diethyl ether (100 ml) and HCl gas bubbled infor 20 minutes, causing the start of precipitation of the product. Theflask was stoppered and left to stand overnight. The product was thenfiltered off as a off-white wax (39–52% yield according to varyingbatches).

¹H NMR (400 MHz, D₂O); 3.8 (s, 3H), 5 (s, 2H), 7.0 (d, 2H), 7.4 (d, 2H).

Intermediate 7: Non-commercial Amidoximes

Method A: e.g. N′-hydroxyethanimidamide (acetamidoxime) (cf. Scheme 2,compound VI)

45 ml of high purity acetonitrile was added to 90 ml of 50%hydroxylamine/50% water (w/w), and stirred with a magnetic stirrer at25° C. Most of the time, crystalline N′-hydroxyethanimidamide separated.The mixture was stirred 24 h at room temperature to complete formationof crystals and filtered the next day. In cases, where no solidseparated initially, a small amount of solution was taken out,evaporated, and the crystals formed used to seed the bulk solution. Theproduct was purified as follows: the crystals were filtered and thendissolved in a non-polar solvent (perfluorohexane) by heating, andcooled overnight at ambient temperature for recrystallization. Thecrystalline material was then filtered and washed with perfluorohexane.The desired product, N′-hydroxyethanimidamide, had a melting point of136° C.–138° C., and the yield approximately 56%.

Method B: e.g. tert-butyl-2-amino-2-(hydroxyimino)ethylcarbamate (Scheme2, compound XI)

Triethylamine (535 μl, 3.84 mmol) was added to a solution of tert-butylcyanomethyl-carbamate (500 mg, 3.20 mmol) and hydroxylaminehydrochloride (227 mg, 3.84 mmol) in ethanol (10 ml). The reactionmixture was then heated overnight at 80° C. The resultant solution wasthen evaporated in vacuo. Ethylacetate (10 ml) was added to the residueand triethylamine hydrochloride was removed by filtration. The solutionwas then evaporated in vacuo to give the crude product.

¹H NMR (360 MHz, DMSO); 1.53 (s, 9H), 3.62–3.63 (d, 2H), 5.33–5.44 (s,2H) 7.10(t, 1H), 8.94(s, 1H).

Similarly, using Method B, and starting from the appropriate commercialcarbonitriles and hydroxylamine hydrochloride, the following, relatedamidoxime intermediates were obtained:(2RS)-N′,2-dihydroxybutanimidamide,(1S,2R)-N′,2-dihydroxycyclohexane-carboximidamide,N′,3-dihydroxypropanimidamide, N′,2-dihydroxyethanimidamide,(2RS)-N′,2-dihydroxy-2-phenylethanimidamide, tert-butyl4-[amino(hydroxyimino)methyl]-1-piperidinecarboxylate, tert-butyl(3RS)-3-[aminohydroxyimino)methyl]-1-piperidinecarboxylate, tert-butyl(2RS)-2-[amino(hydroxyimino)methyl]-1-piperidinecarboxylate, ethylaminohydroxyimino)ethanoate.

Intermediate 8:(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Scheme 8, compound XV)

1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine carboxylic acid(Intermediate 2, 95.9 g, 0.371 mol) was charged into a 3 L flange flask,fitted with an overhead stirrer, nitrogen inlet/outlet and temperatureprobe. Dry THF (1.15 L) was then added to the flask, and the solutionwas cooled to −20° C. prior to adding triethylamine (52 mL, 0.371 mol).The solution was then stirred for 10 minutes. Ethyl chloroformate (35ml, 0.371 mol) was added to the solution over 10 minutes, maintainingthe temperature around −20° C. The reaction was then stirred for afurther 30 minutes at this temperature. A solution of ammonia saturatedTHF solution was prepared by bubbling ammonia through 250 mL of dry THFfor 15 minutes at −78° C. The ammonia solution was added to the reactionflask via cannula over 10 minutes, maintaining the reaction temperaturebelow −25° C. to control the exotherm. The solution was allowed toattain room temperature over 2 hours, and was then stirred for a furtherhour. The solvent was removed from the reaction in vacuo and the residuewas partitioned between dichloromethane (500 mL) and water (500 mL).After separation, the organic layer was washed with 3×250 mL of water,the combined aqueous layers were then washed with 2×250 mL of DCM andthis DCM was back-washed with 100 ml of water. The combined organiclayers were then dried over sodium sulphate, filtered and the solventremoved in vacuo. The desired product, tert-butyl(2S,4EZ)-2-(aminocarbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate,was obtained as a white amorphous solid (85.8 g, 90%).

¹H NMR (400 MHz, DMSO); 1.5 (s, 9H), 2.65 (m, 1H), 3.15 (m, 1H), 3.9 (s,3H), 4.2 (m, 2H), 4.5 (m, 1H), 7.2 (m, 1H), 7.65 (m, 1H).

tert-butyl(2S,4EZ)-2-(aminocarbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate (20g, 77.7 mmol) was charged into a 1 L round bottomed flask under an inertatmosphere. Dry dichloromethane (140 mL) was then added to the flask,followed by TFA (60 mL). The reaction was stirred at room temperaturefor 90 minutes, monitoring the disappearance of starting material by tlc(10% MeOH in DCM). Toluene (200 mL) was then added to the reactionmixture, and the solvents removed in vacuo. The residue was re-dissolvedin DCM (200 mL), cooled to −5° C. and triethylamine (43 mL, 311 mmol)was added (exotherm). [1,1′-biphenyl]-4-carbonyl chloride (16.8 g, 77.7mmol) was added to the reaction mixture, which was stirred at roomtemperature for 1.5 h. At this point, further DCM (500 mL) and 1M HCl(250 mL) was added. The mixture was stirred vigorously and theprecipitate filtered off. The filtrate layers were separated, theorganic layer being washed with 1M HCl (250 mL) and saturatedbicarbonate (250 mL). The basic aqueous layer was back washed with DCM(250 mL), and the combined organics were dried over magnesium sulphate,filtered and the filtrate was concentrated to ca. 200 mL. The resultingslurry was filtered to give the desired product,(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamideas an off-white solid (7.3 g, 28%). A further quantity of less purematerial (7.9 g, 30%) could be obtained by adding hexane (125 mL) to thefiltrate.

¹H NMR (400 MHz, DMSO); 2.6 (m, 1H), 3.2 (m, 1H), 3.8 (m, 3H), 4.1–4.5(m, 2H), 4.9 (m, 1H), 7.2–8.0 (m, 11H).

(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(7.46 g, 22.1 mmol) was charged into a round bottomed flask, pyridine(400 mL) and p-toluenesulfonyl chloride (4.21 g, 22.1 mmol) was added.The resulting suspension was heated to 80° C., for 4 hours. The solventwas removed in vacuo and the residue dissolved in DCM (400 mL), thesolution being washed with 1M HCl (2×75 mL) and saturated bicarbonate(70 mL) before drying over sodium sulphate, filtration and removal ofsolvent in vacuo. Purification by short path silica gel chromatography,eluting initially with dichloromethane to remove less polar material andsubsequently with 1% MEOH in DCM, gave the desired compound,(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbonitrile,as an off-white solid (4.2 g, 60%).

¹H NMR (400 MHz, DMSO); 3.0 (m, 1H), 3.2 (m, 1H), 3.7 (m, 3H), 4.2 (m,1H), 4.5 (m, 1H), 5.4 (m, 1H), 7.4–7.8 (m, 9H).

According to the general method outlined above for the synthesis ofIntermediates 8, triethylamine (1.94 ml, 13.94 mmol) was slowly added toa suspension of(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbonitrile(3.71 g, 11.62 mmol) and hydroxylamine.hydrochloride (0.97 g, 13.94mmol) in ethanol (150 ml), under stirring. The reaction mixture wasallowed to stir at 80° C. for 16 h, and then cooled to ambienttemperatures. The solvent was removed by evaporation and the solid wassuspended in water (100 ml) then filtered. The solid was washed withdiethyl ether (2×100 ml) whilst on the sinter and then dried in vacuo at40° C., to give the desired product,(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(3.35 g, 82%).

¹H-NMR (400 MHz, DMSO): 2.6–2.7 (m, 1H), 2.9–3.1 (m, 1H), 3.6–3.75 (m,3H), 4.0–4.2 (m, 1H), 4.2–4.4 (m, 1H), 4.6 (m, 0.5H), 5.1 (m, 0.5H), 5.5(m, 2H), 7.4–7.8 (m, 9H), 9.2–9.4 (m, 1H).

Intermediate 9: tert-butyl(2S,4EZ)-2-(hydrazinocarbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate(Scheme 10, compound XVII)

A solution was made containing, e.g.,(4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid (Intermediate 2, 17.81 mmoles; 4.6 gr) in a 1:1 mixture of methanoland toluene (250 mL). Trimethylsilyl diazomethane (32.5 mL of a 2Msolution in hexanes, 59 mmol) was then added dropwise to the sirredsolution at room temperature under nitrogen. After completion of theevolution of nitrogen gas, the resulting yellow solution was evaporatedin vacuo, and the residue re-dissolved in DCM and washed with NH₄Clsatand 10% NaHCO₃, and brine, dried over Na₂SO₄ and evaporated in vacuo,giving the desired compound, 1-tert-butyl 2-methyl(2S,4EZ)-4-(methoxyimino)-1,2-pyrrolidinedicarboxylate, as a yellow oil(4.0 g, 83%).

1-tert-butyl 2-methyl(2S,4EZ)-4-(methoxyimino)-1,2-pyrrolidinedicarboxylate (1.95 mmoles; 530mg) was dissolved in 4 mL of MeOH and a solution of 4 mL of MeOH and 1.5mL (d=1.03; 30.86 mmoles) of 80% hydrazine.hydrate was added (finalc(NH₂NH₂)=13%). The reaction mixture was agitated for 2 days. Solventswere evaporated in vacuo and the residue re-dissolved in MeOH andevaporated (3×). The desired compound, tert-butyl(2S,4EZ)-2-(hydrazinocarbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate,was isolated as a yellow oil (500 mg; 94%).

¹H-NMR (CDCl₃): 1.47 (s, 9H, CH3), 2.8–3.2 (m, 2H, CH2), 3.87 (s, 3H,CH3-O), 3.95–4.3 (m, 2H, CH2), 4.52 (m, 1H, CH—N). MS(APCI⁺): 273.0,545.4(2M⁺¹).

Intermediate 10: 2′-methyl[1,1′-biphenyl]-4-carboxylic acid

To a mixture of 4-bromobenzoic acid (30 g, 0.15 mol),2-methylphenylboronic acid (24 g, 0.15 mol), sodium carbonate (250 g) intoluene (500 mL) and water (500 mL) was addedtetrakis-triphenylphosphine palladium(0) (9 g, 0.0074 mol) undernitrogen atmosphere. The reaction mixture was refluxed for 10 h. Afterthis time, 100 ml of 10% NaOH were added to the reaction mixture, theaqueous layer was separated and washed with toluene (2×200 mL).Acidification of the aqueous layer with 3N HCl solution gave a solidproduct, which was filtered, washed with water and dried. The crudeproduct was then crystallised from toluene to yield2′-methyl[1,1′-biphenyl]-4-carboxylic acid (20 g, 62.5%). Conversely,the product could also be obtained from 1-bromo-2-methylbenzene and4-carboxybenzeneboronic acid, using analogous conditions.

¹H NMR (300 MHz, DMSO); 2.2 (s, 3H), 7.2–7.4 (m, 4H), 7.43 (d, J=9 Hz,2H), 7.99 (d, J=9 Hz, 2H), 13 (b, 1H).

Similarly, using the appropriate commercial boronic acids andarylbromides, the following, related intermediate 1,1′-biphenylderivatives (12) were obtained: 4′-methyl[1,1′-biphenyl]-4-carboxylicacid; 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid;2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid;2-methyl[1,1′-biphenyl]-4-carboxylic acid;3-methyl[1,1′-biphenyl]-4-carboxylic acid;2,2′-dimethyl[1,1′-biphenyl]-4-carboxylic acid;2′-methoxy[1,1′-biphenyl]-4-carboxylic acid;3′-methoxy[1,1′-biphenyl]-4-carboxylic acid;4′-methoxy[1,1′-biphenyl]-4-carboxylic acid;2′-chloro[1,1′-biphenyl]-4-carboxylic acid;3′-chloro[1,1′-biphenyl]-4-carboxylic acid;4′-chloro[1,1′-biphenyl]-4-carboxylic acid;3′,4′-dichloro[1,1′-biphenyl]-4-carboxylic acid;2′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid;3′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid;2′-cyano[1,1′-biphenyl]-4-carboxylic acid;2′,4′-difluoro[1,1′-biphenyl]-4-carboxylic acid; 4-(2-pyridinyl)benzoicacid; 4-(3-pyridinyl)benzoic acid; 4-(4-pyridinyl)benzoic acid;4-(5-pyrimidinyl)benzoic acid; and others.

Intermediate 11: 4-(3-methyl-2-pyridinyl)benzoic acid

A mixture of 2-bromo-3-methylpyridine (22.5 g, 0.1312 mol),4-(hydroxymethyl)phenylboronic acid (25 g, 0.164 mol), Pd(PPh₃)₄ (9.5 g,0.0082 mol), and sodium carbonate (200 g in 500 ml of water) in toluene(750 ml) were refluxed under nitrogen atmosphere for 15 h. Separated thetoluene layer and distilled under reduced pressure to give a residue.The residue was then purified by column chromatography to yield[4-(3-methyl-2-pyridinyl)phenyl]methanol (12 g, 47%).

To a solution of [4-(3-methyl-2-pyridinyl)phenyl]methanol (12 g, 0.06mol) in dry DMF (150 mL) was added pyridiniumdichromate (91 g, 0.24 mol)and stirred at RT for 3 days. The reaction mixture was poured into waterand extracted with ethyl acetate (250 mL). The organic layer was washedwith water, brine, dried and concentrated. The crude was purified bycolumn chromatography over silica gel to give4-(3-methyl-2-pyridinyl)benzoic acid (3 g, 25%) as white solid.

¹H NMR (300 MHz, DMSO); 2.3 (s, 3H), 7.33 (dd, J=7.5 Hz, 5 Hz, 1H), 7.67(d, J=8 Hz, 2H), 7.75 (d, J=7.5 Hz, 1H), 8.01 (d, J=8 Hz, 2H), 8.50 (d,J=5 Hz, 1H), 13 (b, 1H).

Intermediate 12: 4-(1-oxido-3-pyridinyl)benzoic acid

To a mixture of 4-tolylboronic acid (38 g, 0.28 mol), 3-bromopyridine(44 g, 0.28 mol), Na₂CO₃ (200 g) in toluene (500 ml) and water (500 ml)was added Pd(PPh₃)₄ (16 g, 0.014 mol), and refluxed for 16 h. Thereaction mixture was cooled, and the separated organic layer was washedwith water and brine, and dried. The solvent was removed to give4-(3-pyridyl)toluene (42 g, 90%).

To a mixture of 4-(3-pyridyl)toluene (35 g, 0.207 mol) in pyridine (400ml) and water (400 ml) was added KMnO₄ (163 g, 1.03 mol) in portions andrefluxed for 12 h. The reaction mixture was filtered through celite andacidified with conc. HCl. The product was washed with water and dried togive 4-(3-pyridyl)benzoic acid (32 g, 76%) as a white solid. To amixture of 4-(3-pyridyl)benzoic acid (22 g, 0.11 mol) in THF (2.51),mCPBA (152 g, 0.44 mol, 50%) was added and stirred at RT for 12 h. Thesolid was filtered, and washed with THF to give4-(1-oxido-3-pyridinyl)benzoic acid (20 g, 86%).

¹H NMR (300 MHz, DMSO); 7.5–7.8 (m, 5H), 7.9 (d, J=8 Hz, 2H), 8.33 (d,J=5 Hz, 2H).

Similarly, starting from 4-tolylboronic acid (45 g, 0.33 mol) and2-bromopyridine (52 g, 0.33 mol), the related intermediate4-(1-oxido-2-pyridinyl)benzoic acid was obtained.

Example 1 General procedure for the solution-phase synthesis ofpyrrolidine oxadiazole derivatives of general formula I, with B=IIa(Schemes 1,11):(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime;(3E,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime and(3Z,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime

a) Protocol for the Formation of the Oxadiazole Ring

Diisopropylcarbodiimide (3.16 g, 25.17 mmol) was added to a solution of(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2, 6.50 g, 25.17 mmol) and acetamidoxime(Intermediate 7, 1.86 g, 25.17 mmol) in DCM (55 ml) and stirredovernight at room temperature (DCM-insoluble amidoximes werepre-dissolved in THF, to which was added a solution of DIC andIntermediate 2 in DCM). After filtering at the pump, and evaporation invacuo, the residue was dissolved in pyridine (60 ml) and refluxed forone hour, then cooled and allowed to stand overnight, then evaporated invacuo. The crude product was then dissolved in DCM (50 ml) and washedwith sat. NaHCO₃(aq) (2×50 ml) and then 1M HCl(aq) (2×50 ml), dried overmagnesium sulphate and evaporated in vacuo (crude yield 70%). Silica gelchromatography, eluting with 15% ethyl acetate in hexanes gave thedesired compound, tert-butyl(2S,4EZ)-4-(methoxyimino)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-1-pyrrolidinecarboxylate(4.4 g, 60% yield).

¹H NMR (360 MHz, DMSO); 1.3–1.6 (d, 9H), 2.4 (s, 3H), 2.8–3.4 (m, 2H),3.9 (s, 3H), 4.3 (s, 2H), 5.2–5.4 (m, 1H).

b) Protocol for the N-deprotection Step

A solution was made containing tert-butyl(2S,4EZ)-4-(methoxyimino)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-1-pyrrolidinecarboxylate(1.26 g, 4.25 mmol) in anhydrous DCM (120 ml). At 0° C., HCl gas,previously dried with a H₂SO₄ cc trap, was bubbled slowly through thereaction and deprotection was monitored by TLC using cyclohexane/ethylacetate (1/1) and stained with a pancaldi solution. After approximately45 minutes, TLC showed no remaining starting materiel and DCM was thenevaporated under vacuo without heating to avoid pyrolidine saltdecomposition. More DCM (20 ml) was then added and evaporated againunder vacuo to remove remaining potential HCl (2–3 times). The desiredproduct, (3EZ,5S)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime, hydrochloride salt, was isolated as a white solid andused without further purification and characterization

c) Protocols for the N-capping Step

Method A: To a solution of(3EZ,5S)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime, hydrochloride salt (200 mg, 0.86 mmol) in DCM (5 ml) wasadded [1,1′-biphenyl]-4-carbonyl chloride (205 mg, 0.95 mmol) followedby diisopropylethylamine (314 μl, 1.81 mmol) and stirred overnight atroom temperature. Aminomethyl polystyrene resin (250 mg) was added tothe reaction mixture and stirred for one hour before filtering at thepump. The solution was washed with citric acid(aq) (2×5 ml) and thendried over MgSO₄, and evaporated in vacuo. The product,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime, was purified by silica gel chromatography, eluting with20% ethylacetate in hexanes (60 mg, 19% yield)

Method B: A solution was made containing(3EZ,5S)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime, hydrochloride salt, 2′-methyl[1,1′-biphenyl]-4-carboxylicacid (0.857 g, 4.04 mmol, 0.95 eq) and, optionally, DMAP (1.03 g, 8.50mmol. 2.0 eq) in dry DCM (120 ml). The reaction was stirred at RT for 10minutes before being cooled down to 0° C. At 0° C., EDC, HCl (815 mg,4.25 mmol) was slowly added portion wise over a 30 minute period. Thereaction mixture was stirred at 0° C. for 2 hours and gently warmed toRT overnight. Once the reaction was completed, the organic phase waswashed twice with citric acid (10%) and sodium carbonate (10%). Theorganic phase was dried and evaporated. The crude product was purifiedand separated into the (E)- and (Z)-isomers by column chromatography(Biotage system, column 40M, 90 g SiO2, using cyclohexane/ethyl acetate(1/1) as eluent affording(3E,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime (770 mg, 34%) colorless oil, 97.5% purity by HPLC) and(3Z,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime (740 mg, 33%), colorless oil, 98.3% purity by HPLC).

(3E,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime: oil; ¹H NMR (300 MHz, CDCl₃): 2.28 (s, 3H, ArCH₃), 2.42(s, 3H, CH₃), 3.03–3.32 (m, 2H), 3.88 (s, 3H, NOCH₃), 4.38–4.59 (m, 2H),6.03 (m, 1H), 7.22–7.29 (m, 5H, H arom.), 7.40–7.44 (m, 2H, H arom.),7.55 (m, 1H); MS(APCI⁺): 391.5; MS(APCI⁻): 389.2.

(3Z,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime: white solid, m.p. 146.5° C.; IR (neat) ν 2936, 1645,1583, 1408, 1323, 1047, 890 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): 2.28 (s, 3H,ArCH₃), 2.42 (s, 3H, CH₃), 3.03–3.32 (m, 2H), 3.88 (s, 3H, NOCH₃),4.38–4.59 (m, 2H), 6.03 (m, 1H), 7.22–7.29 (m, 5H, H arom.), 7.40–7.44(m, 2H, H arom.), 7.55 (m, 1H); MS(APCI⁺): 391.5; MS(APCI⁻): 389.2

Example 2(3EZ,5S)-1-[(2′-chloro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime

Following the general methods as outlined in Example 1 (Method B),starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), N′-hydroxyethanimidamide (Intermediate 7) and2′-chloro[1,1′-biphenyl]-4-carboxylic acid (Intermediate 10), the titlecompound was isolated, after flash-chromatography, as a mixture ofE-/Z-isomers as an oil in 31% yield (98.5% purity by HPLC).

Oil; ¹H NMR (300 MHz, CDCl₃): 2.41 (s, 3H, CH₃), 2.96–3.31 (m, 2H, CH₂),3.87 (s, 3H, NOCH₃), 4.31–4.59 (m, 2H, CH₂), 6.03 (m, 1H), 7.30 (s, 3H,H arom.), 7.50–7.64 (m, 5H, H arom.); MS(ESI⁺): 411.2; MS(ESI⁻): 408.9.

Example 3(3EZ,5S)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-1-{[2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-3-pyrrolidinoneO-methyloxime

Following the general methods as outlined in Example 1 (Method B),starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), N′-hydroxyethanimidamide (Intermediate 7) and2′-(trifluoromethyl) [1,1′-biphenyl]-4-carboxylic acid (Intermediate10), the title compound was isolated, after flash-chromatography, as amixture of E-/Z-isomers as an oil in 44% yield (88.2% purity by HPLC).

Oil; ¹H NMR (300 MHz, CDCl₃): 2.40 (s, 3H, CH₃), 2.88–3.31 (m, 2H, CH₂),3.87 (s, 3H, NOCH₃), 4.27–4.53 (m, 2H, CH₂), 6.03 (m, 1H), 7.27–7.70 (m,7H, H arom.), 7.77 (m, 1H, H arom.); MS(ESI⁺): 445.4; MS(ESI⁻): 443.1.

Example 4(3E,5S)-1-[(2′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime and(3Z,5S)-1-[(2′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime

Following the general methods as outlined in Example 1 (Method B),starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), N′-hydroxyethanimidamide (Intermediate 7) and2′-fluoro[1,1′-biphenyl]-4-carboxylic acid (Intermediate 10), the titlecompounds were obtained as a mixture of E-/Z-isomers and subsequentlyseparated by flash-chromatography, to afford(3E,5S)-1-[(2′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime in 11% yield (95.0% purity by HPLC) and(3Z,5S)-1-[(2′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime in 11% yield (98.2% purity by HPLC).

(3E,5S)-1-[(2′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime: oil; ¹H NMR (300 MHz, CDCl₃): 2.42 (s, 3H, CH₃),3.07–3.25 (m, 2H, CH₂), 3.87 (s, 3H, NOCH₃), 4.42–4.52 (m, 2H, CH₂),6.04 (m, 1H), 7.15–7.29 (m, 2H, H arom.), 7.30–7.44 (m, 2H, H arom.),7.70 (m, 4H); MS(ESI⁺): 395.0; MS(ESI⁻): 393.0.

(3Z,5S)-1-[(2′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime: oil; ¹H NMR (300 MHz, CDCl₃): 2.42 (s, 3H, CH₃), 3.02 (m,1H, CH), 3.25 (m, 1H, CH), 3.87 (s, 3H, NOCH₃), 4.34–4.58 (m, 2H, CH₂),6.04 (m, 1H), 7.15–7.29 (m, 2H, H arom.), 7.30–7.44 (m, 2H, H arom.),7.70 (m, 4H); MS(ESI⁺): 395.0; MS(ESI⁻): 393.0.

Example 5(3EZ,5S)-1-[(4′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime

Following the general methods as outlined in Example 1 (Method B),starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), N′-hydroxyethanimidamide (Intermediate 7) and4′-fluoro[1,1′-biphenyl]-4-carboxylic acid (Intermediate 10), the titlecompound was isolated, after flash-chromatography, as a mixture ofE-/Z-isomers as an oil in 32% yield (94.1% purity by HPLC).

Oil; ¹H NMR (300 MHz, CDCl₃): 2.42 (s, 3H, CH₃), 2.95–3.30 (m, 2H, CH₂),3.87 (s, 3H, NOCH₃), 4.27–4.55 (m, 2H, CH₂), 6.02 (m, 1H), 7.12 (m, 2H,H arom.), 7.27–7.61 (m, 6H, H arom.); MS(ESI⁺): 395.5; MS(ESI⁻): 393.4.

Example 6(3EZ,5S)-1-[(2′-chloro-4′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime;(3Z,5S)-1-[(2′-chloro-4′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime

Following the general methods as outlined in Example 1 (Method B),starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), N′-hydroxyethanimidamide (Intermediate 7) and2′-chloro-4′-fluoro [1,1′-biphenyl]-4-carboxylic acid (Intermediate 10),the title compound was isolated, after flash-chromatography, as amixture of E-/Z-isomers as an oil in 60% overall yield (95.20% purity byHPLC). Subsequent flash-chromatography afforded(3Z,5S)-1-[(2′-chloro-4′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime in 30% yield (97.5% purity by HPLC).

(3EZ,5S)-1-[(2′-chloro-4′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime: oil; ¹H NMR (300 MHz, CDCl₃): 2.31 (s, 3H, CH₃),2.78–3.24 (m, 2H, CH₂), 3.77 (s, 3H, NOCH₃), 4.30–4.52 (m, 2H, CH₂);5.93 (m, 1H), 6.88–7.60 (m, 7H, H arom.); MS(ESI⁺): 429.20.

(3Z,5S)-1-[(2′-chloro-4′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime: oil; ¹H NMR (300 MHz, CDCl₃): 2.31 (s, 3H, CH₃),2.78–3.24 (m, 2H, CH₂), 3.77 (s, 3H, NOCH₃), 4.30–4.52 (m, 2H, CH₂),5.93 (m, 1H), 6.88–7.60 (m, 7H, H arom.); MS(ES): 429.20.

Example 7(3EZ,5S)-1-[(2′,4′-difluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime;(3Z,5S)-1-[(2′,4′-difluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime;(3E,5S)-1-[(2′,4′-difluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime

Following the general methods as outlined in Example 1 (Method B),starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), N′-hydroxyethanimidamide (Intermediate 7) and2′,4′-difluoro [1,1′-biphenyl]-4-carboxylic acid (Intermediate 10), thetitle compound was isolated, after flash-chromatography, as a mixture ofE-/Z-isomers as an oil in a 37% overall yield (98.6% purity by HPLC).Subsequent flash-chromatographic separation of E- and Z-isomers afforded(3Z,5S)-1-[(2′,4′-difluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime in 15% yield (98.5% purity by HPLC), and(3E,5S)-1-[(2′,4′-difluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime in 13% yield (97.5% purity by HPLC).

(3EZ,5S)-1-[(2′,4′-difluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime: oil; ¹H NMR (300 MHz, CDCl₃): 2.34 (s, 3H, CH₃),2.86–3.25 (m, 2H, CH₂), 3.79 (s, 3H, NOCH₃), 4.30–4.52 (m, 2H, CH₂),5.96 (m, 1H), 6.82–7.01 (m, 2H, H arom), 7.32–7.66 (m, 5H, H arom);MS(ESI⁺): 413.40; MS(ESI^(−):) 411.20.

(3Z,5S)-1-[(2′,4′-difluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime: oil; ¹H NMR (300 MHz, CDCl₃): 2.31 (s, 3H, CH₃),2.78–3.24 (m, 2H, CH₂), 3.77 (s, 3H, NOCH₃), 4.30–4.52 (m, 2H, CH₂),5.93 (m, 1H), 6.88–7.60 (m, 7H, H arom.); MS(ESI⁺): 413.40; MS(ESI⁻):411.20.

(3E,5S)-1-[(2′,4′-difluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime: oil; ¹H NMR (300 MHz, CDCl₃): 2.31 (s, 3H, CH₃),2.78–3.24 (m, 2H, CH₂), 3.77 (s, 3H, NOCH₃), 4.30–4.52 (m, 2H, CH₂),5.93 (m, 1H), 6.88–7.60 (m, 7H, H arom.); MS(ESI⁺): 413.40; MS(ESI⁻):411.20.

Example 8(3EZ,5S)-1-[(4′-fluoro-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime

Following the general methods as outlined in Example 1 (Method B),starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), N′-hydroxyethanimidamide (Intermediate 7) and4′-fluoro-2′-methyl[1,1′-biphenyl]-4-carboxylic acid (Intermediate 10),the title compound was isolated, after flash-chromatography, as amixture of E-/Z-isomers as an oil in a 14% overall yield (95.2% purityby HPLC).

Oil; ¹H NMR (300 MHz, CDCl₃): 2.17 (s, 3H, CH₃), 2.34 (s, 3H, CH₃),2.86–3.26 (m, 2H, CH₂), 3.80 (s, 3H, NOCH₃), 4.33–4.45 (m, 2H, CH₂),5.97 (m, 1H), 6.82–6.95 (m, 2H, H arom), 7.10–7.66 (m, 5H, H arom);MS(ESI⁺): 409.33; MS(ESI⁻): 407.11.

Example 9(3E,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime;(3Z,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime

Following the general methods as outlined in Example 1 (Method B),starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), N′,3-dihydroxypropanimidamide (Intermediate 7)and [1,1′-biphenyl]-4-carboxylic acid (Intermediate 10), the titlecompound was isolated, after flash-chromatography, as a mixture ofE-/Z-isomers as an oil in 64% overall yield (90% purity by HPLC). Atthis stage, a scavenging purification using pol-trisamine in DCM(Novabiochem) was carried out to remove excess acid by-products whichturned out to be difficult to remove by flash chromatography column. TheE- and Z-isomers were finally deparated by flash column chromatography(Biotage system, column 40M, 90 g SiO₂, using cyclohexane/ethyl acetate(2/8) as eluent, affording(3E,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime in 25% yield (98.0% purity by HPLC), and(3Z,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime in 25% yield (99.5% purity by HPLC).

(3E,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime: white solid, mp. 140.5° C.; ¹H NMR (300 MHz, CDCl₃):2.98–3.05 (m, 3H, CH₂), 3.33 (m, 1H, CH₂), 3.86 (s, 3H, OCH₃), 4.35–4.57(m, 2H, CH₂), 6.04 (m, 1H, CH), 7.38–7.51 (m, 3H, H_(-Ar).), 7.51–7.61(m, 6H, H_(-Ar).); M⁺(ESI⁺): 407.31; M(ESI⁻): 405.13.

(3Z,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime: white solid, m.p. 141° C.; ¹H NMR (300 MHz, CDCl₃):2.98–3.05 (m, 3H, CH₂), 3.33 (m, 1H, CH₂), 3.86 (s, 3H, OCH₃), 4.35–4.57(m, 2H, CH₂), 6.04 (m, 1H, CH), 7.38–7.51 (m, 3H, H_(-Ar).), 7.51–7.61(m, 6H, H_(-Ar).); M⁺(ESI⁺): 407.31; M(ESI⁻): 405.13.

Example 102-{5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-3-yl}ethyl[(tert-butoxycarbonyl)amino]acetate;2-{5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-3-yl}ethylaminoacetate

EDC (290 mg, 1.51 mmol) was added portion-wise (over 15 minutes) to astirred solution of(3Z,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime (1.59 mmol, Example 9), dimethylamino pyridine (185 mg,1.51 mmol), and [(tert-butoxycarbonyl)amino]acetic acid (264 mg, 1.51mmol) in DCM (50 ml) at 0° C. After stirring for 1 hour at 0° C., thereaction mixture was allowed to warm to room temperature. The reactionwas monitored by TLC and LC/MS. After a further hour stirring at RT, thereaction mixture was hydrolyzed with water, washed with citric acid 10%(2×10 ml) then Na₂CO₃ (aq) (2×10 ml), dried over MgSO₄ and evaporated invacuo to give the crude product. Silica gel chromatography, eluting with40% EtOAc in cyclohexane gave the desired compound,(2-{5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-3-yl}ethyl[(tert-butoxycarbonyl)amino]acetate)as a mixture of E- and Z-isomers in 90% yield (purity by HPLC: 93.6%).

M⁺(ESI⁺): 564.61; M(ESI⁻): 562.60

(2-{5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-3-yl}ethyl[(tert-butoxycarbonyl)amino]acetate)(100 mg, 0.178 mmol) was treated with a 25% TFA/DCM solution at 0° C.for 1 hour. The reaction was then slowly made basic at 0° C. with sodiumcarbonate solution (10%) and extracted with DCM. The organic phases werecombined and dried over magnesium sulfate and solvent removal affordedthe desired compound,2-{5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-3-yl}ethylaminoacetate, as an oil in a 70% yield (94.6% purity by HPLC).

M⁺(ESI⁺): 464.17; M(ESI⁻): 462.86

Example 11(3EZ,5S)-1-[(2′-chloro-4′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime

Following the general methods as outlined in Example 1 (Method B),starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), N′,3-dihydroxypropanidamide (Intermediate 7) and2′-chloro-4′-fluoro[1,1′-biphenyl]-4-carboxylic acid (Intermediate 10),the title compound was isolated, after flash-chromatography, as amixture of E-/Z-isomers as an oil in 8% overall yield (78.7% purity byHPLC).

Oil; ¹H NMR (300 MHz, CDCl₃): 2.93 (m, 2H, CH₂), 3.10–3.25 (m, 2H, CH₂),3.80 (s, 3H, NOCH₃), 4.34–4.45 (m, 2H, CH₂), 5.98 (m, 1H), 6.90–7.05 (m,2H, H arom), 7.20–7.66 (m, 5H, H arom); MS(ESI⁺): 459.12; MS(ESI⁻):457.07.

Example 12 tert-butyl4-{5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-3-yl}-1-piperidinecarboxylate;(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime

Following the general methods as outlined in Example 1 (Method A),starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (intermediate 2), tert-butyl4-[amino(hydroxyimino)methyl]-1-piperidinecarboxylate (Intermediate 7)and [1,1′-biphenyl]-4-carbonyl chloride, the desired compound,tert-butyl4-{5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-3-yl}-1-piperidinecarboxylate,was isolated, after flash-chromatography (cyclohexane/ethylacetate 6/4),as a mixture of E-/Z-isomers in 60% yield (97.9% purity by HPLC).

Oil; ¹H NMR (300 MHz, CDCl₃): 1.47 (s, 9H, CH₃), 1.60–2.10 (m, 4H, CH₂),2.90–3.02 (m, 2H, CH₂), 3.30–3.40 (m, 1H, CH), 3.86 (s, 3H, NOCH₃),4.01–4.55 (m, 6H, CH₂N), 6.03 (m, 1H), 7.48–7.64 (m, 9H, H arom.);MS(ESI⁺): 546.4; MS(ESI⁻): 544.2.

tert-butyl4-{5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-3-yl}-1-piperidinecarboxylate)(100 mg, 1.80 mmol) was treated with a 25% TFA/DCM solution at 0° C. for1 hour. The reaction was then made basic with a sodium carbonatesolution (10%) and extracted with DCM. The organic phases were combinedand dried over magnesium sulfate and solvent removal afforded a residuewhich was purified by flash-chromatography usingcyclohexane/ethylacetate (2/8) as eluent to give(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime as a mixture of E-/Z-isomers in 80% yield (96.1% purity byHPLC).

Oil; ¹H NMR (300 MHz, CDCl₃): 1.80–2.20 (m, 4H, CH₂), 2.90–3.50 (m, 8H,CH₂), 3.87 (s, 3H, NOCH₃), 4.30–4.60 (m, 2H, CH₂), 6.04 (m, 1H, CH),7.48–7.64 (m, 9H, H arom.); MS(ESI⁺): 446.4.

Example 13(3EZ,5S)-5-[3-(1-acetyl-4-piperidinyl)-1,2,4-oxadiazol-5-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime

(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime (Example 12) was dissolved in dry DCM at 0° C. in presenceof 1.5 equivalent of triethyl amine and treated with 1 equivalent ofacetyl chloride. The reaction mixture was stirred at this temperaturefor 30 minutes and then hydrolyzed with ice. The reaction was then madebasic with a sodium carbonate solution (10%) and extracted with DCM. Itwas then dried with magnesium sulfate and solvent removal afforded aresidue which was purified by flash-chromatography usingcyclohexane/ethylacetate (1/1) as eluent to give(3EZ,5S)-5-[3-(1-acetyl-4-piperidinyl)-1,2,4-oxadiazol-5-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime as a mixture of E-/Z-isomers in 95% yield (100% purity byHPLC).

Oil; ¹H NMR (300 MHz, CDCl₃): 1.70–2.20 (m, 8H, CH₃CO, CH₂), 2.89–3.40(m, 6H, CH₂), 3.88 (s, 3H, NOCH₃), 4.40–4.60 (m, 2H, CH₂), 6.04 (m, 1H,CH), 7.48–7.64 (m, 9H), H arom.); MS(ESI⁺): 488.37; MS(ESI⁻): 486.17.

Example 14(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(1-methyl-4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime

(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime (Example 12) was dissolved in dry DCM at 0° C. in presenceof 1.5 equivalent of triethyl amine and treated with 1 equivalent ofmethyl iodide. The reaction mixture was stirred at room temperature for12 hours. The reaction was hydrolysed and then made basic with a sodiumcarbonate solution (10%) and extracted with DCM. It was then dried withmagnesium sulfate and solvent removal afforded a residue, which waspurified by flash-chromatography using dichloromethane/methanol (98/2)as eluent to give(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(1-methyl-4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime as a mixture of E-/Z-isomers in 50% yield (96.8% purity byHPLC).

Oil; ¹H NMR (300 MHz, CDCl₃): 1.19 (m, 2H, CH₂), 2.14–2.70 (m, 8H, CH₃,CH₂), 2.89–3.25 (m, 4H, CH₂), 3.80 (s, 3H, NOCH₃), 4.20–4.55 (m, 2H,CH₂), 5.94 (m, 1H, CH), 7.33–7.58 (m, 9H, H arom.); MS(ESI⁺): 460.43;MS(ESI⁻): 458.24.

Example 15 General procedure for the solution-phase synthesis ofpyrrolidine oxadiazole derivatives of general formula I, with B being asubstituent of formula IIb (see Schemes 7,11):(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(phenoxymethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime

To a suspension of(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8, 100 mg, 0.28 mmol), DMAP (41 mg, 0.34 mmol), andphenoxyacetic acid (48 mg, 0.31 mmol) in DCM & DMF (1:1, 10 ml) wasadded EDC (59 mg, 0.31 mmol). After stirring overnight at ambienttemperature, the solvent was evaporated in vacuo. The residue wasdissolved in DCM (10 ml) and washed with citric acid(aq) (2×10 ml)followed by sodium bicarbonate(aq) (2×10 ml). After evaporating invacuo, pyridine was added (15 ml) and the solution was refluxedovernight. The pyridine was removed in vacuo, and the residue wasdissolved in DCM (10 ml), washed with citric acid(aq) (2×10 ml), driedover magnesium sulphate and evaporatedm, to afford the title compound in80% purity by HPLC. MS(ESI⁺): m/z=469.2.

Example 16{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methylformamide

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and (formylamino)acetic acid, the title compound wasobtained in 72% purity by HPLC.

¹H-NMR (400 MHz, CDCl₃): 2.9–3.2 (m, 2H), 3.8 (m, 3H), 4.2–4.4 (m, 2H0,4.6 (m, 2H), 5.9 (m, 1H), 7.0 (m, 1H), 7.3–7.7 (m, 9H), 8.2 (s, 1H).MS(ESI⁺): m/z=420.1.

Example 17(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(methoxymethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and methoxyacetic acid, the title compound was obtainedin 91% purity by HPLC.

¹H-NMR (400 MHz, CDCl₃): 2.9–3.2 (m, 2H), 3.4 (s, 3H), 3.75 (m, 3H),4.2–4.5 (m, 2H), 4.6 (s, 2H), 6.0 (m, 1H0, 7.4–7.6 (m, 9H). MS(ESI⁺):m/z=407.2.

Example 18(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-phenyl-1,2,4-oxadiazol-3-yl)-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and benzoic acid, the title compound was obtained in85% purity by HPLC. MS(ESI⁺): m/z=439.2.

Example 19N-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)acetamide

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and (acetylamino)acetic acid, the title compound wasobtained in 72% purity by HPLC. MS(ESI⁺): m/z=434.2.

Example 20(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[4-(hydroxymethyl)phenyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and 4-(hydroxymethyl)benzoic acid, the title compoundwas obtained in 54% purity by HPLC. MS(ESI⁺): m/z=469.4.

Example 21(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(2-hydroxyethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and 3-hydroxypropanoic acid, the title compound wasobtained in 61% purity by HPLC. MS(ESI⁺): m/z=407.2.

Example 22(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(2S)-2-hydroxy-2-phenylethyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and (3S)-3-hydroxy-3-phenylpropanoic acid, the titlecompound was obtained in 89% purity by HPLC. MS(ESI⁺): m/z=483.3.

Example 23(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(2-phenoxyethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and 3-phenoxypropanoic acid, the title compound wasobtained in 84% purity by HPLC. MS(ESI⁺): m/z=483.3.

Example 24(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(2-methoxyethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and 3-methoxypropanoic acid, the title compound wasobtained in 80% purity by HPLC. MS(ESI⁺): m/z=421.1.

Example 25(3EZ,5S)-5-[5-(1-acetyl-4-piperidinyl)-1,2,4-oxadiazol-3-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and 1-acetyl-4-piperidinecarboxylic acid, the titlecompound was obtained in 87% purity by HPLC. MS(ESI⁺): m/z=488.4.

Example 26(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and 2-pyridinecarboxylic acid, the title compound wasobtained in 82% purity by HPLC. MS(ESI⁺): m/z=440.2.

Example 27(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(3-thienyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and 3-thiophenecarboxylic acid, the title compound wasobtained in 64% purity by HPLC. MS(ESI⁺): m/z=445.2.

Example 28(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and propionic acid, the title compound was obtained in47% purity by HPLC. MS(ESI⁺): m/z=391.1.

Example 29(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-cyclopentyl-1,2,4-oxadiazol-3-yl)-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and cyclopentanecarboxylic acid, the title compound wasobtained in 62% purity by HPLC. MS(ESI⁺): m/z=431.1.

Example 30(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and acetic acid, the title compound was obtained in 76%purity by HPLC. MS(ESI⁺): m/z=377.0.

Example 31(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(RS)-hydroxy(phenyl)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and (2RS)-hydroxy(phenyl)ethanoic acid, the titlecompound was obtained in 73% purity by HPLC. MS(ESI⁺): m/z=469.3.

Example 32(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(1RS)-1-hydroxy-2-phenylethyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and (2RS)-2-hydroxy-3-phenylpropanoic acid, the titlecompound was obtained in 78% purity by HPLC. MS(ESI⁺): m/z=483.3.

Example 33(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(1R)-1-(dimethylamino)-2-phenylethyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and (2R)-2-(dimethylamino)-3-phenylpropanoic acid, thetitle compound was obtained in 54% purity by HPLC. MS(ESI⁺): m/z=510.6.

Example 34(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(3-pyridinyl-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and 3-pyridinecarboxylic acid, the tide compound wasobtained in 78% purity by HPLC. MS(ESI⁺): m/z=440.2.

Example 35(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(6-hydroxy-3-pyridinyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and 6-hydroxynicotinic-acid, the title compound wasobtained in 50% yield (90% purity by HPLC).

¹H NMR (300 MHz, CDCl₃): 2.90–3.30 (m, 2H, CH₂), 3.86 (s, 3H, NOCH₃),4.30–4.60 (m, 2H, CH₂), 6.04 (m, 1H, CH), 6.70 (d, 1H, H arom),7.40–7.70 (m, 9H, H arom.); 8.10 (d, 1H, H arom), 8.40 (d, 1H, H arom);MS(ESI⁺): 456.4; MS(ESI⁻): 454.2.

Example 36(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(dimethylamino)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime;(3Z,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(dimethylamino)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime;(3E,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(dimethylamino)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and (dimethylamino)acetic acid, the title compound wasobtained in 50% overall yield (96% purity by HPLC) as a micture of E-and Z-isomers. Flash-chromatographic separation afforded the pureZ-isomer in a 23% yield (98.5% purity by HPLC), and the pure E-isomer in20% yield (98.2% purity by HPLC).

(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(dimethylamino)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime: ¹H NMR (300 MHz, CDCl₃): 2.42 (s, 6H, CH₃), 2.90–3.30 (m,2H, CH₂), 3.86 (s, 3H, NOCH₃), 4.30–4.60 (m, 2H, CH₂), 6.01 (m, 1H, CH),7.40–7.70 (m, 9H, H arom.); MS(ESI⁺): 420.4.

(3Z,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(dimethylamino)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime: ¹H NMR (300 MHz, CDCl₃): 2.42 (s, 6H, CH₃), 2.90–3.30 (m,2H, CH₂), 3.86 (s, 3H, NOCH₃), 4.30–4.60 (m, 2H, CH₂), 6.01 (m, 1H, CH),7.40–7.70 (m, 9H, H arom.); MS(ESI⁺): 420.4.

(3E,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(dimethylamino)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime: ¹H NMR (300 MHz, CDCl₃): 2.42 (s, 6H, CH₃), 2.90–3.30 (m,2H, CH₂), 3.86 (s, 3H, NOCH₃), 4.30–4.60 (m, 2H, CH₂), 6.01 (m, 1H, CH),7.40–7.70 (m, 9H, H arom.); MS(ESI⁺): 420.4.

Example 374-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-2,6-piperazinedione

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and (3,5-dioxo-1-piperazinyl)acetic acid, the titlecompound was obtained in 55% yield (99.0% purity by HPLC).

¹H NMR (300 MHz, CDCl₃): 2.80–3.30 (m, 2H, CH₂), 3.61 (s, 4H, CH₂), 3.86(s, 3H, NOCH₃), 4.09 (m, 2H, CH₂), 4.30–4.60 (m, 2H, CH₂), 6.02 (m, 1H,CH), 7.42–7.75 (m, 9H, H arom), 8.56 (m, 1H, NH); MS(ESI⁺): 489.20;MS(ESI⁻): 487.17.

Example 38(3EZ,5S)-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[2-(dimethylamino)ethyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and N,N-dimethyl-β-alanine, the title compound wasobtained in 25% yield (91.5% purity by HPLC).

¹H NMR (300 MHz, CDCl₃): 2.31 (s, 6H, CH₃), 2.80–3.40 (m, 6H, CH₂), 3.88(s, 3H, NOCH₃), 4.30–4.60 (m, 2H, CH₂), 6.03 (m, 1H, CH), 7.40–7.63 (m,9H, H arom.); MS(ESI⁺): 434.4.

Example 39 tert-butyl(4S)-4-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}-4-[(tert-butoxycarbonyl)amino]butanoate

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and(2S)-5-tert-butoxy-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid,the title compound was obtained in 75% yield (78.9% purity by HPLC).

¹H NMR (300 MHz, CDCl₃): 1.31 (s, 18H, CH₃), 2.05–2.45 (m, 4H, CH₂),2.70–2.95 (m, 2H, CH₂), 3.87 (s, 3H, NOCH₃), 4.30–4.55 (m, 2H, CH₂),5.10 (m, 1H, CH), 6.03 (m, 1H, CH), 7.40–7.63 (m, 9H, H arom.);MS(ESI⁺): 620.3, MS(ESI⁻): 618.3.

Example 40(3EZ,5RS)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(1-methyl-3-piperidinyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and 1-methyl-3-piperidinecarboxylic acid, the titlecompound was obtained in 72% yield (99.2% purity by HPLC).

¹H NMR (300 MHz, CDCl₃): 1.60–1.80 (m, 3H, CH, CH₂), 2.05–2.15 (m, 2H,CH₂), 2.33 (s, 3H, CH₃); 2.92–3.22 (m, 6H, CH₂), 3.84 (s, 3H, NOCH₃),4.34–4.50 (m, 2H, CH₂), 6.01 (m, 1H, CH), 7.38–7.63 (m, 9H, H arom.);MS(ESI⁺): 460.5

Example 41(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(1-methyl-4-piperidinyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-1-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and 1-methyl-4-piperidinecarboxylic acid, the titlecompound was obtained in 85% yield (96.9% purity by HPLC).

¹H NMR (300 MHz, CDCl₃): 1.98–2.14 (m, 5H, CH, CH₂), 2.32 (s, 3H, CH₃),2.89–3.20 (m, 6H, CH₂), 3.86 (s, 3H, NOCH₃), 4.34–4.50 (m, 2H, CH₂),6.02 (m, 1H, CH), 7.38–7.63 (m, 9H, H arom.); MS(ESI⁺): 460.4

Example 42(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-vinyl-1,2,4-oxadiazol-3-yl)-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and acrylic acid, this compound was obtained in 20%yield (89.4% purity by HPLC).

¹H NMR (300 MHz, CDCl₃): 2.85–3.15 (m, 2H, CH₂), 3.78 (s, 3H, NOCH₃),4.28–4.44 (m, 2H, CH₂), 5.89 (m, 2H, CH), 6.45 (d, 1H, CH), 6.53 (d, 1H,CH), 7.30–7.56 (m, 9H, H arom.); MS(ESI⁺): 389.2.

Example 43 tert-butyl(3R)-3-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}-1-piperidinecarboxylate;(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(3R)-piperidinyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and (3R)-1-(tert-butoxycarbonyl)-3-piperidinecarboxylicacid, the title compound, tert-butyl(3R)-3-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}-1-piperidinecarboxylate,was obtained in 85% yield (96.5% purity by HPLC).

MS(ESI⁺): 546.5.

tert-butyl(3R)-3-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}-1-piperidinecarboxylate(100 mg, 1.80 mmol) was treated with a 25% TFA/DCM solution at 0° C. for1 hour. The reaction was then made basic with a sodium carbonatesolution (10%) and extracted with DCM. The organic phases were combinedand dried over magnesium sulfate and solvent removal afforded a residue,which was purified by flash-chromatography usingdichloromethane/methanol as eluent to give the desired product,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(3R)-piperidinyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime, as a mixture of E-/Z-isomers in a 80% yield (95.7% purityby HPLC).

¹H NMR (300 MHz, CDCl₃): 1.62–1.92 (m, 3H, CH₂), 2.20–2.42 (m, 2H, CH₂),2.75–3.41 (m, 7H, CH₂), 3.86 (s, 3H, NOCH₃), 4.36–4.51 (m, 2H, CH₂),6.02 (m, 1H, CH), 7.40–7.64 (m, 9H, H arom); MS(ESI⁺): 446.2.

Example 44(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(3)-1-methylpiperidinyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime

A solution containing 1 equivalent of(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(3R)-piperidinyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime (Example 43), dissolved in dry DCM at 0° C. in presence of1.5 equivalent of triethyl amine, was reacted with 1 equivalent ofmethyl iodide. The reaction mixture was stirred at room temperature for12 hours. The reaction was hydrolyzed and then made basic with sodiumcarbonate solution (10%) and extracted with DCM. The organic phase wasthen dried with magnesium sulfate, and concentrated in vacuo to give aresidue which was purified by flash-chromatography usingdichloromethane/methanol as eluent to give the expected product,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(3R)-1-methylpiperidinyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime, as a mixture of E-/Z-isomers, in 45% yield (97.6% purityby HPLC).

¹H NMR (300 MHz, CDCl₃): 1.61–1.90 (m, 3H, CH₂), 2.01–2.20 (m, 3H, CH₂),2.23 (m, 3H, CH₃), 2.70–3.30 (m, 5H, CH₂), 3.77 (s, 3H, NOCH₃),4.30–4.52 (m, 2H, CH₂), 6.01 (m, 1H, CH), 7.38–7.70 (m, 9H, H arom.);MS(ESI⁺): 460.2.

Example 45 tert-butyl(3S)-3-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}-1-piperidinecarboxylate;(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(3S)-piperidinyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and (3S)-1-(tert-butoxycarbonyl)-3-piperidinecarboxylicacid, the title compound, tert-butyl(3S)-3-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}-1-piperidinecarboxylate,was obtained in 85% yield (97.20% purity by HPLC).

MS(ESI⁺): 546.5

tert-butyl(3S)-3-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}-1-piperidinecarboxylate(100 mg, 1.80 mmol) was treated with a 25% TFA/DCM solution at 0° C. for1 hour. The reaction was then made basic with a sodium carbonatesolution (10%) and extracted with DCM. The organic phases were combinedand dried over magnesium sulfate and solvent removal afforded a residue,which was purified by flash-chromatography usingdichloromethane/methanol as eluent to give the desired product,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(3S)-piperidinyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime, as a mixture of E-/Z-isomers in a 85% yield (95.1% purityby HPLC).

¹H NMR (300 MHz, CDCl₃): 1.62–1.92 (m, 3H, CH₂), 2.20–2.42 (m, 2H, CH₂),2.75–3.41 (m, 7H, CH₂), 3.86 (s, 3H, NOCH₃), 4.36–4.51 (m, 2H, CH₂),6.02 (m, 1H, CH), 7.40–7.64 (m, 9H, H arom); MS(ESI⁺): 446.2.

Example 46(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(3S)-1-methylpiperidinyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime

A solution containing 1 equivalent of(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(3S)-piperidinyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime (Example 45), dissolved in dry DCM at 0° C. in presence of1.5 equivalent of triethyl amine, was reacted with 1 equivalent ofmethyl iodide. The reaction mixture was stirred at room temperature for12 hours. The reaction was hydrolyzed and then made basic with sodiumcarbonate solution (10%) and extracted with DCM. The organic phase wasthen dried with magnesium sulfate, and concentrated in vacuo to give aresidue which was purified by flash-chromatography usingdichloromethane/methanol as eluent to give the expected product,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(3S)-1-methylpiperidinyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime, as a mixture of E-/Z-isomers, in 55% yield (97.9% purityby HPLC).

¹H NMR (300 MHz, CDCl₃): 1.61–1.90 (m, 3H, CH₂), 2.01–2.20 (m, 3H, CH₂),2.33 (m, 3H, CH₃), 2.70–3.30 (m, 5H, CH₂), 3.84 (s, 3H, NOCH₃),4.30–4.52 (m, 2H, CH₂), 6.01 (m, 1H, CH), 7.38–7.70 (m, 9H, H arom.);MS(ESI⁺): 460.2.

Example 47 tert-butyl4-(2-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}ethyl)-1-piperazinecarboxylate

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and 3-[4-(tert-butoxycarbonyl)-1-piperazinyl]propanoicacid, the title compound was obtained in 70% yield (78% purity by HPLC).

¹H NMR (300 MHz, CDCl₃): 1.38 (s, 9H, CH₃), 2.38 (m, 4H, CH₂), 2.70–2.85(m, 6H, CH₂), 3.34 (m, 4H, CH₂), 3.84 (s, 3H, NOCH₃), 4.23–4.42 (m, 2H,CH₂), 5.92 (m, 1H, CH), 7.19–7.53 (m, 9H, H arom.); MS(ESI⁺): 575.5.

Example 48 tert-butyl4-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-1-piperazinecarboxylate;(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(1-piperazinylmethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and [4-(tert-butoxycarbonyl)-1-piperazinyl]acetic acid,the title compound, tert-butyl4-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-1-piperazinecarboxylate,was obtained in 75% yield (88% purity by HPLC).

¹H NMR (300 MHz, CDCl₃): 1.38 (s, 9H, CH₃), 2.38 (m, 4H, CH₂), 2.70–2.85(m, 4H, CH₂), 3.34 (m, 4H, CH₂), 3.84 (s, 3H, NOCH₃), 4.23–4.42 (m, 2H,CH₂), 5.92 (m, 1H, CH), 7.19–7.53 (m, 9H, H arom.); MS(ESI⁺): 561.5.

tert-butyl4-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-1-piperazinecarboxylate(100 mg, 1.80 mmol) was treated with a 25% TFA/DCM solution at 0° C. for1 hour. The reaction was then made basic with a sodium carbonatesolution (10%) and extracted with DCM. The organic phases were combinedand dried over magnesium sulfate and solvent removal afforded a residue,which was purified by flash-chromatography usingdichloromethane/methanol as eluent to give the desired product,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(1-piperazinylmethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime, as a mixture of E-/Z-isomers in a 85% yield (94.3% purityby HPLC).

¹H NMR (300 MHz, CDCl₃): 2.50 (m, 4H, CH₂), 2.85–2.87 (m, 4H, CH₂),3.04–3.19 (m, 2H, CH₂), 3.76 (s, 5H, CH₂, NOCH₃), 4.27–4.42 (m, 2H,CH₂), 5.94 (m, 1H, CH), 7.20–7.54 (m, 9H, H arom.); MS(ESI⁺): 461.2.

Example 49(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(4-methyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime;(3Z,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(4-methyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime

A solution containing 1 equivalent of(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(1-piperazinylmethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime (Example 48), dissolved in dry DCM at 0° C. in presence of1.5 equivalent of triethyl amine, was reacted with 1 equivalent ofmethyl iodide. The reaction mixture was stirred at room temperature for12 hours. The reaction was hydrolyzed and then made basic with sodiumcarbonate solution (10%) and extracted with DCM. The organic phase wasthen dried with magnesium sulfate, and concentrated in vacuo to give aresidue which was purified by flash-chromatography usingdichloromethane/methanol as eluent to give the expected product,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(4-methyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime, as a mixture of E-/Z-isomers, in 50% yield (99.9% purityby HPLC). The pure Z-isomer could be separated by flash-chromatography,and was obtained in 31% yield (98.9% purity by HPLC).

(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(4-methyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime: ¹H NMR (300 MHz, CDCl₃): 2.32 (s, 3H, CH₃), 2.50–3.20 (m,10H, CH₂), 3.78–3.92 (m, 5H, CH₂; NOCH₃), 4.27–4.45 (m, 2H, CH₂); 5.95(m, 1H, CH), 7.32–7.57 (m, 9H, H arom); MS(ESI⁺): 475.2.

(3Z,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(4-methyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime: ¹H NMR (300 MHz, CDCl₃): 2.32 (s, 3H, CH₃), 2.50–3.20 (m,10H, CH₂), 3.78–3.92 (m, 5H, CH₂; NOCH₃), 4.27–4.45 (m, 2H, CH₂), 5.95(m, 1H, CH), 7.32–7.57 (m, 9H, H arom); MS(ESI⁺): 475.2.

Example 50(3EZ,5S)-5-{5-[(4-acetyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime;(3Z,5S)-5-{5-[(4-acetyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime

To a solution containing 1 equivalent of(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(1-piperazinylmethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime (Example 48) in dry DCM at 0° C. were added 1.5 equivalentof triethyl amine and 1 equivalent of acetyl chloride. The reactionmixture was stirred at this temperature for 30 minutes and thenhydrolyzed with ice. The reaction was then made basic with a sodiumcarbonate solution (10%) and extracted with DCM. The organic phase wasdried with magnesium sulfate and solvent removal afforded a residuewhich was purified by flash-chromatography to give the expected product,(3EZ,5S)-5-{5-[(4-acetyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime as a mixture of E-/Z-isomers, in 70% yield (94.4% purityby HPLC). The pure Z-isomer could be separated by flash-chromatographyusing cyclohexane/ethylacetate (1/1) as eluent, and was obtained in 40%yield (98.0% purity by HPLC).

(3EZ,5S)-5-{5-[(4-acetyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime: ¹H NMR (300 MHz, CDCl₃): 2.09 (m, 3H, CH₃), 2.65 (s, 4H,CH₂), 2.90–3.20 (m, 2H, CH₂), 3.54 (m, 2H, CH₂), 3.71 (m, 2H, CH₂),3.85–3.92 (m, 5H, CH₂; NOCH₃), 4.36–4.50 (m, 2H, CH₂), 6.02 (m, 1H, CH),7.40–7.75 (m, 9H, H arom); MS(ESI⁺): 503.2.

(3Z,5S)-5-{5-[(4-acetyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime: ¹H NMR (300 MHz, CDCl₃): 2.09 (3H CH₃), 2.65 (s, 4H,CH₂), 2.90–3.20 (m, 2H, CH₂), 3.54 (m, 2H, CH₂), 3.71 (m, 2H, CH₂),3.85–3.92 (m, 5H, CH₂; NOCH₃), 4.36–4.50 (m, 2H, CH₂), 6.02 (m, 1H, CH),7.40–7.75 (m, 9H, H arom); MS(ESI⁺): 503.2.

Example 504-{[(2S,4EZ)-2-(5-{[(tert-butoxycarbonyl)amino]methyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and [(tert-butoxycarbonyl)amino]acetic acid, the titlecompound was obtained in 80% yield (78.2% purity by HPLC).

¹H NMR (300 MHz, CDCl₃): 1.48 (s, 9H, CH₃), 1.58 (s, 2H, CH₂), 2.90–3.43(m, 2H, CH₂), 3.85 (s, 3H, NOCH₃), 4.20–4.60 (m, 2H, CH₂), 6.03 (m, 1H,CH), 7.37–7.63 (m, 9H, H arom.); MS(ESI⁺): 492.20, MS(ESI⁻): 490.2.

Example 51N-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-3-(1-piperidinyl)propanamide

4-{[(2S,4EZ)-2-(5-{[(tert-butoxycarbonyl)amino]methyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl(Example 50) was treated with a 25% TFA/DCM solution at 0° C. Thereaction was monitored by LC/MS and stopped after completion. Thereaction was then made basic with sodium carbonate solution (10%) andextracted with DCM. The combined organic phases were dried overmagnesium sulfate. Solvent removal afforded a crude product, which wasused without purification in the next step. The residue was dissolved inDCM at room temperature, DMAP (1.1 equivalent) and3-(1-piperidinyl)propanoic acid (1 equivalent) were added. The reactionmixture was then cooled down to 0° C. and EDC (1.1 equivalent) was addedportion-wise. After stirring for 1 hour at 0° C., the reaction mixturewas allowed to warm to room temperature. The reaction was monitored byTLC and LC/MS. Usually after 12 hours stirring at RT, the reactionmixture was hydrolyzed, washed with sodium carbonate solution (10%),dried over MgSO₄, and evaporated in vacuo to give a crude product. Flashchromatography on silica gel, eluting with 60% EtOAc in hexane, gave thetitle compound as a mixture of E- and Z-isomers in 50% yield (87.4%purity by HPLC).

MS(ESI⁺): 531.5; MS(ESI⁻): 529.2.

Example 52N-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-3-(dimethylamino)propanamide

4-{[(2S,4EZ)-2-(5-{[(tert-butoxycarbonyl)amino]methyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl(Example 50) was treated with a 25% TFA/DCM solution at 0° C. Thereaction was monitored by LC/MS and stopped after completion. Thereaction was then made basic with sodium carbonate solution (10%) andextracted with DCM. The combined organic phases were dried overmagnesium sulfate. Solvent removal afforded a crude product, which wasused without purification in the next step. The residue was dissolved inDCM at room temperature, DMAP (1.1 equivalent) andN,N-dimethyl-β-alanine (1 equivalent) were added. The reaction mixturewas then cooled down to 0° C. and EDC (1.1 equivalent) was addedportion-wise. After stirring for 1 hour at 0° C., the reaction mixturewas allowed to warm to room temperature. The reaction was monitored byTLC and LC/MS. Usually after 12 hours stirring at RT, the reactionmixture was hydrolyzed, washed with sodium carbonate solution (10%),dried over MgSO₄, and evaporated in vacuo to give a crude product. Flashchromatography on silica gel, eluting with 60% EtOAc in hexane, gave thetitle compound as a mixture of E- and Z-isomers in 52% yield (82% purityby HPLC).

MS(ESI⁺): 491.2.

Example 53N-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-2-(dimethylamino)acetamide

4-{[(2S,4EZ)-2-(5-{[(tert-butoxycarbonyl)amino]methyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl(Example 50) was treated with a 25% TFA/DCM solution at 0° C. Thereaction was monitored by LC/MS and stopped after completion. Thereaction was then made basic with sodium carbonate solution (10%) andextracted with DCM. The combined organic phases were dried overmagnesium sulfate. Solvent removal afforded a crude product, which wasused without purification in the next step. The residue was dissolved inDCM at room temperature, DMAP (1.1 equivalent) and (dimethylamino)aceticacid (1 equivalent) were added. The reaction mixture was then cooleddown to 0° C. and EDC (1.1 equivalent) was added portion-wise. Afterstirring for 1 hour at 0° C., the reaction mixture was allowed to warmto room temperature. The reaction was monitored by TLC and LC/MS.Usually after 12 hours stirring at RT, the reaction mixture washydrolyzed, washed with sodium carbonate solution (10%), dried overMgSO₄, and evaporated in vacuo to give a crude product. Flashchromatography on silica gel, eluting with 60% EtOAc in hexane, gave thetitle compound as a mixture of E- and Z-isomers in 45% yield (88.1%purity by HPLC).

MS(ESI⁺): 477.25: MS(ESI⁻): 475.15.

Example 544-{[(2S,4EZ)-2-(5-{2-[(tert-butoxycarbonyl)amino]ethyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and N-(tert-butoxycarbonyl)-β-alanine, this compoundwas obtained in 75% yield (91.9% purity by HPLC).

¹H NMR (300 MHz, CDCl₃): 1.36 (s, 9H, CH₃), 2.80–3.15 (m, 4H, CH₂), 3.51(m, 2H, CH₂), 3.78 (s, 3H, NOCH₃), 4.27–4.42 (m, 2H, CH₂), 5.93 (m, 1H,CH), 7.39–7.56 (m, 9H, H arom.); MS(ESI⁺): 506.20, MS(ESI⁻): 504.2.

Example 554-{[(2S,4EZ)-2-(5-{(1S)-2-tert-butoxy-1-[(tert-butoxycarbonyl)amino]ethyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl;(3EZ,5S)-5-{5-[(1S)-1-amino-2-tert-butoxyethyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime;(3EZ,5S)-5-{5-[(1S)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and(2S)-3-tert-butoxy-2-[(tert-butoxycarbonyl)amino]propanoic acid, thetitle compound,4-{[(2S,4EZ)-2-(5-{(1S)-2-tert-butoxy-1-[(tert-butoxycarbonyl)amino]ethyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carboxyl}-1,1′-biphenyl,was obtained in 44% yield (89.4% purity by HPLC).

MS(ESI⁺): 578.5.

4-{[(2S,4EZ)-2-(5-{(1S)-2-tert-butoxy-1-[(tert-butoxycarbonyl)amino]ethyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl(100 mg, 1.80 mmol) was treated with a 25% TFA/DCM solution at 0° C. for1 hour. The reaction was then made basic with a sodium carbonatesolution (10%) and extracted with DCM. The organic phases were combinedand dried over magnesium sulfate and solvent removal afforded twoproducts, which were separated and purified by flash-chromatography togive the desired products as mixtures of E-/Z-isomers,(3EZ,5S)-5-{5-[(1S)-1-amino-2-tert-butoxyethyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl-3-pyrrolidinoneO-methyloxime in 20% yield (80.8% purity by HPLC), and(3EZ,5S)-5-{5-[(1S)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime in 30% yield (98.1% purity by HPLC).

(3EZ,5S)-5-{5-[(1S)-1-amino-2-tert-butoxyethyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime: ¹H NMR (300 MHz, CDCl₃): 1.07 (s, 9H, CH₃), 1.96 (m, 2H,NH₂), 2.83–3.18 (m, 2H, CH₂), 3.64–3.78 (m, 5H, CH₂, NOCH₃), 4.23–4.43(m, 2H, CH₂), 5.96 (m, 1H, CH), 7.30–7.56 (m, 9H, H arom); MS(ESI⁺):478.0.

(3EZ,5S)-5-{5-[(1S)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime: ¹H NMR (300 MHz, CDCl₃): 2.90–3.15 (m, 2H, CH₂), 3.86 (s,3H, NOCH₃), 4.05–4.42 (m, 4H, CH₂), 4.81 (m, 1H, CH), 5.89 (m, 1H, CH),7.36–7.62 (m, 9H, H arom); MS(ESI⁺): 422.20; MS(ESI⁻): 420.1.

Example 564-{[(2S,4EZ)-2-(5-{(1S,2R)-2-tert-butoxy-1-[(tert-butoxycarbonyl)amino]propyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl;(3EZ,5S)-5-{5-(1S,2R)-1-amino-2-hydroxypropyl-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 15, starting from(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8) and(2S,3R)-3-tert-butoxy-2-[(tert-butoxycarbonyl)amino]butanoic acid, thetitle compound,4-{[(2S,4EZ)-2-(5-{(1S,2R)-2-tert-butoxy-1-[(tert-butoxycarbonyl)amino]propyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl,was obtained in 48% yield (85.9% purity by HPLC).

MS(ESI⁺): 592.7

4-{[(2S,4EZ)-2-(5-{(1S,2R)-2-tert-butoxy-1-[(tert-butoxycarbonyl)amino]propyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl(100 mg, 1.80 mmol) was treated with a 25% TFA/DCM solution at 0° C. for1 hour. The reaction was then made basic with a sodium carbonatesolution (10%) and extracted with DCM. The organic phases were combinedand dried over magnesium sulfate and solvent removal afforded a residue,which was purified by flash-chromatography usingdichloromethane/methanol as eluent to give the desired product,(3EZ,5S)-5-{5-[(1S,2R)-1-amino-2-hydroxypropyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime, as a mixture of E-/Z-isomers in 30% yield (90.3% purityby HPLC).

¹H NMR (300 MHz, CDCl₃): 1.24–1.35 (m, 4H, CH₃, CH), 2.94–3.25 (m, 2H,CH₂), 3.83 (s, 3H, NOCH₃), 4.22–4.50 (m, 3H, CH, CH₂), 6.01 (m, 1H, CH),7.38–7.60 (m, 9H, H arom); MS(ESI⁺): 436.3.

Example 57 ethyl5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazole-3-carboxylate

Following the general methods as outlined in Example 1 (Method B),starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), ethyl amino(hydroxyimino)ethanoate (Intermediate7) and [1,1′-biphenyl]-4-carboxylic acid, the title compound wasisolated, after flash-chromatography, as a mixture of E-/Z-isomers as anoil in 35% yield (96.1% purity by HPLC).

¹H NMR (300 MHz, CDCl₃): 1.35 (t, 3H), 2.9–3.3 (m, 2H), 3.8 (m, 3H),4.2–4.60 (m, 4H), 6.01 (s, 1H), 7.25–7.60 (m, 9H); MS(ESI⁺): 435.3.

Example 585-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-N-[3-(dimethylamino)propyl]-1,2,4-oxadiazole-3-carboxamide

Ethyl5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazole-3-carboxylate(187 mg, 0.43 mmol, Example 57) was dissolved in 3:1 THF:water (10 mL)and stirred. LiOH (20 mg, 0.47 mmol, 1.1 eq) was added and the mixturestirred for 2 hours at room temperature. THF was removed in vacuo, theresidue diluted in water and the solution acidified with 6N HCl (2drops, pH=5). The aqueous phase was extracted with DCM (2×10 mL). Theorganic phase was dried with magnesium sulfate and the solvent removedin vacuo to give the acid derivative (165 mg, 94%) as a yellow oil. Thiscrude intermediate (102 mg, 0.25 mmol) was dissolved in DCM (5 mL) andcooled to 0° C. EDC.HCl (53 mg, 0.28 mmol, 1.1 eq) was added in oneportion and the mixture stirred for 10 minutes.N′,N′-dimethyl-1,3-propanediamine (35 mg, 0.28 mmol, 1.1 eq) was addedand the solution stirred at room temperature over night. The mixture wasthen washed with 10% aqueous citric acid (2×5 mL). The separation wasnot good due to the partial solubility of the compound in water. Organicsolvent was removed in vacuo and the residue was purified bysemi-prep-LC to give the title compound in 56% yield (93% purity byHPLC).

¹H NMR (300 MHz, CDCl₃): 2.0–2.1 (m, 2H), 2.8 (s, 6H), 2.9–3.3 (m, 4H),3.5 (m, 2H), 3.8 (m, 3H), 4.2–4.60 (m, 4H), 5.9 (s, 1H), 7.25–7.65 (m,9H), 7.8 (m, 1H); MS(ESI⁺): 491.4.

Example 59 General Procedure for the Solid-Phase Synthesis ofPyrrolidine Oxadiazole Derivatives of General Formula I, with B Being aSubstituent of Formula IIa (see Scheme 13)

a) Loading Step

A solution of(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2, 26 g, 100 mmol) in dry DCM (150 ml) was added toKaiser oxime resin (34.97 g, 50 mmol) which was suspended in dry DCM(200 ml). Diisopropylcarbodiimide (7.83 ml, 50 mmol) was then added tothe suspension and shaken overnight at ambient temperatures. The resinwas then filtered at the pump and washed sequentially with DMF, DCM andfinally diethyl ether before drying at 40° C. in vacuo.

b) N-deprotection Step

The resin obtained in the loading step was shaken with a 20% solution oftrifluoroacetic acid in dichloromethane (200 ml) for 30 minutes prior tofiltering at the pump and washing sequentially with aliquots of DMF, DCMand finally diethyl ether before drying at room temperature in vacuo.

c) N-capping Step

The resin from the previous step was transferred into a 96-wellfilter-plate (approx. 50 mg of dry resin/well) and each well treatedwith an N-reactive derivatising agent, e.g. with either of the followingsolutions:

-   a) an acid chloride (0.165 mmol) and diisopropylethylamine (0.165    mmol) in dry dichloromethane (1 ml), overnight-   b) an acid (0.165 mmol) and DIC (0.165 mmol) in, depending on the    solubility of the carboxylic acid, dry dichloromethane or NMP (1 ml)    overnight-   c) an isocyanate (0.165 mmol) in dry THF (1 ml), overnight-   d) a sulfonyl chloride (0.165 mmol) and diisopropylethylamine (0.165    mmol) in NMP (1 ml), overnight.-   e) a benzyl (alkyl) bromide (0.165 mmol) and diisopropylethylamine    (0.165 mmol) in NMP (1 ml), overnight.

The plate was then sealed and shaken overnight at ambient temperature.The resins were then filtered, washing the resin sequentially withaliquots of DMF, DCM and finally diethyl ether before drying at roomtemperature in vacuo.

d) Cleavage Step

The amidoxime component (e.g., Intermediates 7, 0.27 mmol) was added tosuspensions of the functionalised oxime resin batches from the previousstep (50 mg, 0.05 mmol) in DCM (0.5–1 ml), the plates sealed and shakenover the weekend period (˜66 hours) at ambient temperatures. Afterfiltration, the resultant solvent was evaporated in vacuo. Pyridine(0.5–1 ml) was added to the residue and the solution was refluxedovernight. After cooling to ambient temperature, the solution wasevaporated in vacuo and the residues re-dissolved in DCM (0.5–1 ml).After a wash with 2×0.5–1 ml 1M HCl_((aq)), the solutions were driedover magnesium sulphate and evaporated in vacuo to give the crudeproducts, which were analyzed by HPLC and mass spectroscopy. In caseswhere an N-Boc-protecting group was present on the oxadiazolesubstituent (e.g. Examples 40, 46–48), a solution of 25% TFA in DCM (3ml) was added to the crude compound (typically 0.15 mmol) and stirred atambient temperatures for 40 min. The solvent was then removed in vacuoto give the N-deprotected products.

Example 60(3EZ,5S)-5-(3-benzyl-1,2,4-oxadiazol-5-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 59, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, andN′-hydroxy-2-phenylethanimidamide, the title compound was obtained in86% purity by HPLC. MS(ESI⁺): m/z=453.2.

Example 61(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(3-{[(2-furylmethyl)sulfanyl]methyl}-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 59, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, and2-[(2-furylmethyl)sulfanyl]-N′-hydroxyethanimidamide, the title compoundwas obtained in 53% purity by HPLC. MS(ESI⁺): m/z=489.6.

Example 62(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 59, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, and(1Z)-N′-hydroxy-3-oxo-3-(1-pyrrolidinyl)propanimidamide, the titlecompound was obtained in 89% purity by HPLC.

MS(ESI⁺): m/z=474.2.

Example 63(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(2-pyridinysulfanyl)methyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 59, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, andN′-hydroxy-2-(2-pyridinylsulfanyl) ethanimidamide, the title compoundwas obtained in 66% purity by HPLC. MS(ESI⁺): m/z=486.2.

Example 64(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 59, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, and4-fluoro-N′-hydroxybenzenecarboximidamide, the title compound wasobtained in 79% purity by HPLC. MS(ESI⁺): m/z=457.2.

Example 65(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(2-thienylsulfanyl)methyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 59, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, andN′-hydroxy-2-(2-thienylsulfanyl) ethanimidamide, the title compound wasobtained in 81% purity by HPLC. MS(ESI⁺): m/z=491.4.

Example 66(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 59, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, and3-(3,5-dimethyl-1H-pyrazol-1-yl)-N′-hydroxy-propanimidamide, the titlecompound was obtained in 79% purity by HPLC. MS(ESI⁺): m/z=485.3.

Example 67(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(methylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 59, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, andN-hydroxy-2-(methylsulfonyl)ethanimidamide, the title compound wasobtained in 87% purity by HPLC. MS(ESI⁺): m/z=455.2.

Example 68(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(5-methyl-3-isoxazolyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 59, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, andN′-hydroxy-5-methyl-3-isoxazole-carboximidamide, the title compound wasobtained in 78% purity by HPLC. MS(ESI⁺): m/z=444.2.

Example 69(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-thienylmethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 59, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, andN′-hydroxy-2-(2-thienyl)ethanimidamide, the title compound was obtainedin 85% purity by HPLC. MS(ESI⁺): m/z=459.2.

Example 70(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(3-phenyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 59, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, andN′-hydroxybenzenecarboximidamide, the title compound was obtained in 82%purity by TPLC. MS(ESI⁺): m/z=439.2.

Example 71(3EZ,5S)-([1,1′-biphenyl]-4-ylcarbonyl)-5-(3-{[(2-furylmethyl)sulfonyl]methyl}-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 59, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, and2-[(2-furylmethyl)sulfonyl]-N′-hydroxy-ethanimidamide, the titlecompound was obtained in 88% purity by HPLC. MS(ESI⁺): m/z=521.4.

Example 72(3EZ,5S)-5-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 59, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, andtert-butyl (2Z)-2-amino-2-(hydroxyimino)ethylcarbamate (an Intermediate7), the title compound was obtained in 85% purity by HPLC. MS(ESI⁺):m/z=392.0.

Example 73(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(RS)-hydroxy(phenyl)methyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 59, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, and(2RS)-N′,2-dihydroxy-2-phenylethanimidamide (an Intermediate 7), thetitle compound was obtained in 75% purity by HPLC. MS(ESI⁺): m/z=469.3.

Example 74(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(1RS)-1-hydroxypropyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 59, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, and(2RS)-N′,2-dihydroxybutanimidamide (an Intermediate 7), the titlecompound was obtained in 79% purity by HPLC. MS(ESI⁺): m/z=421.2.

Example 75(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-hydroxymethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 59, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, andN′,2-dihydroxyethanimidamide (an Intermediate 7), the title compound wasobtained in 85% purity by HPLC. MS(ESI⁺): m/z=393.0.

Example 76(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(1S,2R)-2-hydroxycyclohexyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 59, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, and(1S,2R)-N′,2-dihydroxycyclohexane-carboximidamide (an Intermediate 7),the title compound was obtained in 85% purity by HPLC. MS(ESI⁺):m/z=461.2.

Example 77(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(3RS)-piperidinyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 59, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, andtert-butyl (3RS)-3-[amino(hydroxyimino)methyl]-1-piperidinecarboxylate(an Intermediate 7), the title compound was obtained in 77% purity byHPLC. MS(ESI⁺): m/z=446.2.

Example 78(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(2RS)-piperidinyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 59, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid (Inter-mediate 2), [1,1′-biphenyl]-4-carbonyl chloride, andtert-butyl (2RS)-2-[aminohydroxyimino)methyl]-1-piperidinecarboxylate(an Intermediate 7), the title compound was obtained in 78% purity byHPLC. MS(ESI⁺): m/z=446.2.

Example 79 General procedure for the solution-phase synthesis ofpyrrolidine oxadiazole derivatives of general formula I, with B being asubstituent of formula III, X=S (Schemes 9,11):(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3-pyrrolidinoneO-methyloxime

To a solution of tert-butyl(2S,4EZ)-2-(hydrazinocarbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate(Intermediate 9, 2.86 mmoles; 780 mg) in ethanol (25 mL) at 0° C. wasadded carbon disulfide (6.86 mmoles; 522 mg) and potassium hydroxide (3mmoles; 168 mg). The mixture was refluxed for 7 h. The solvent wasevaporated and the residue re-dissolved in EtOAc and washed with NH₄Clsat and 10% NaHCO₃ and brine. The organic layer was dried over Na₂SO₄and evaporated to give the desired N-protected intermediate, tert-butyl(2S,4EZ)-4-(methoxyimino)-2-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1-pyrrolidine-carboxylate,as a yellowish oil (200 mg, 23%).

¹H-NMR (CDCl₃): 1.46 (m, 9H, CH3), 2.7–3.3 (m, 2H, CH2), 3.88 (s, 3H,CH3-O), 4.05–4.35 (m, 2H, CH2), 5.29 (m, 1H, CH—N). MS(APCI⁻): 313.0.

The N-protected intermediate from the previous step, tert-butyl(2S,4EZ)-1-(methoxyimino)-2-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1-pyrrolidinecarboxylate(0.64 mmoles; 200 mg), was dissolved in dry DCM (25 mL) at 0° C. and HClgas was bubbled into the solution for 20 min. The solvent was evaporatedand the residue re-dissolved in DCM and evaporated. The residue wasagain re-dissolved in dried DCM (20 mL) and triethylamine (5.12 mmoles;518 mg) was added, followed by slow addition of the N-capping agent,e.g. of [1,1′-biphenyl]-4-carbonyl chloride (0.64 mmoles; 139 mg),previously dissolved in DCM at 0° C.; the reaction mixture was stirredat r.t. overnight. To the mixture was then added 200 mg of Pol-trisamine(3.45 mmol/g) to scavenge the acyl chloride and the reaction wasagitated for an additional 5 h, then filtered and the filtrate waswashed with NH₄Clsat and brine, dried over Na₂SO₄ and the solventevaporated The crude product was purified by FC using a linear gradient40:60 (EtOAc:Cyclohexane) to 90:10 (EtOAc:MeOH) on the flash master for37 minutes, to afford the title compound,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3-pyrrolidinoneO-methyloxime (40 mg, 16%).

¹H-NMR (CDCl₃): 2.8–3.2 (m, 2H, CH2), 3.9 (s, 3H, CH3-O), 4.2–4.5 (m,2H, CH2), 5.95 (m, 1H, CH—N), 7.3–7.7 (m, 9H, Ar). MS(APCI⁺): 395.0;MS(APCI⁻): 393.0.

Example 80 General procedure for the solution-phase synthesis ofpyrrolidine oxadiazole derivatives of general formula I, with B=III, X=O(Schemes 9,11):5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,3,4-oxadiazol-2(3H)-one

To a stirring solution of tert-butyl(2S,4EZ)-2-(hydrazinocarbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate(Intermediate 9, 1.84 mmoles; 500 mg) and triethylamine (2.76 mmoles; 27mg) in THF (25 mL) at 0° C. was added 1,1′-carbonyldiimidazole (2.76mmoles, 448 mg). The stirring was continued for 5 hours. Another portionof triethylamine and 1,1′-carbonyldiimidazole were added and stirringwas continued at room temperature overnight. The solvent was evaporatedand the residue was dissolved in EtOAc and washed with NH₄Clsat., and10% NaHCO₃, and brine. The organic layer was dried over Na₂SO₄ andevaporated to dryness to give the desired N-protected intermediate,tert-butyl(2S,4E)-4-(methoxyimino)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1-pyrrolidinecarboxylate,as a white foam (460 mg, 84%).

¹H-NMR (CDCl₃): 1.46 (s, 9H, CH3), 2.8–3.25 (m, 2H, CH2), 3.88 (s, 3H,CH3-O), 4.05–4.35 (m, 2H, CH2), 5.06 (m, 1H, CH—N). MS(APCI⁻): 297.0.

The N-protected intermediate from the previous step, tert-butyl(2S,4E)-4-(methoxyimino)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1-pyrrolidinecarboxylatewas subjected to identical conditions for N-deprotection and subsequentN-acylation, as described in Example 49, affording, afterflash-chromatographic purification, the title compound,(5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-pyrrolidinyl]-1,3,4-oxadiazol-2(3H)-one(130 mg, 26%).

¹H-NMR (CDCl₃): 2.8–3.1 (m, 2H, CH2), 3.84 (s, 3H, CH3-O), 4.2–4.5 (m,2H, CH2), 5.75 (m, 1H, CH—N), 7.35–7.7 (m, 9H, Ar). MS(APCI⁺): 379.0;MS(APCI⁻): 377.0.

Example 81 General procedure for the solution-phase synthesis ofpyrrolidine oxadiazole derivatives of general formula I, with B being asubstituent of formula IV, X=bond, R⁸=H (Schemes 9,11):(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(1,3,4-oxadiazol-2-yl)-3-pyrrolidinoneO-methyloxime

To a solution of tert-butyl(2S,4EZ)-2-(hydrazinocarbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate(Intermediate 9, 2.86 mmoles; 780 mg) in TMOF (8 mL) were added 3 dropsof acetic acid, and the reaction mixture was heated to 80° C. for 4 h,then at room temperature overnight. The solvent was evaporated todryness to give a yellowish foam (610 mg). The residue was redissolvedin toluene and P₂O₅ was added. The reaction mixture was heated to refluxfor 2.5 h, after which time the solvent was evaporated. To the residuewas added water, and the solution was extracted with EtOAc. The organiclayer was washed with NH₄Clsat and brine to give the desired N-protectedintermediate, tert-butyl(2S,4E)-4-(methoxyimino)-2-(1,3,4-oxadiazol-2-yl)-1-pyrrolidinecarboxylate,as a yellow oil (330 mg, 63%). ¹H-NMR-analysis revealed that the productwas present in >90% purity. The compound was considered pure enough tobe used for the subsequent steps without further purification (only 2spots on TLC, Pancaldi revealation, corresponding to the E- andZ-isomers, R_(f)=0.35 and 0.47, eluting with EtOAc:Hexane 1:1).

¹H-NMR (CDCl₃): 1.46 (broad m, 9H, CH3), 2.8–3.3 (m, 2H, CH2), 3.89 (s,3H, CH3-O), 4.05–4.3 (m, 2H, CH2), 5.4 (m, 1H, CH—N). MS(APCI⁺): 283.0.

The N-protected intermediate from the previous step, tert-butyl(2S,4E)-4-(methoxyimino)-2-(1,3,4-oxadiazol-2-yl)-1-pyrrolidinecarboxylatewas subjected to identical conditions for N-deprotection and subsequentN-acylation, as described in Example 49, affording, afterflash-chromatographic purification, the title compound,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(1,3,4-oxadiazol-2-yl)-3-pyrrolidinoneO-methyloxime (80 mg, 10%).

¹H-NMR (CDCl₃): 2.8–3.2 (m, 2H, CH2), 3.65 (s, 3H, CH3-O), 4.2–4.45 (m,2H, CH2), 5.95 (m, 1H, CH—N), 7.3–7.6 (m, 9H, Ar), 8.2 (s, 1H, CHhetero). MS(APCI⁺): 363.4.

Example 82 General procedure for the solution-phase synthesis ofpyrrolidine oxadiazole derivatives of general formula I, with B being asubstituent of formula IIb, R⁷=H:(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(1,2,4-oxadiazol-3-yl)-3-pyrrolidinoneO-methyloxime

To a suspension of(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide(Intermediate 8, 170 mg, 0.48 mmol) in TMOF (20 ml), a catalytic amountof p-toluenesulfonic acid was added and the reaction mixture was heatedto reflux for 16 h. TMOF was then evaporated in vacuo and the residuedissolved in DCM (15 mls). This was washed with NaHCO₃(aq) (2×15 ml),dried over MgSO₄ and evaporated in vacuo. Silica gel chromatographyeluting with 15% EtOAc in hexanes gave the desired product,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(1,2,4-oxadiazol-3-yl)-3-pyrrolidinoneO-methyloxime (59 mg).

¹H-NMR (400 MHz, CDCl₃): 2.9 (m, 1H), 3.2 (m, 1H), 3.9 (m, 3H), 4.3–4.6(m, 2H), 6.1 (m, 1H), 7.3–7.7 (m, 9H, 8.7 (s, 1H). MS(APCI⁺): 363.2.

Example 83 Preparation of a Pharmaceutical Formulation

Formulation 1—Tablets

A pyrrolidine oxadiazole compound of formula I is admixed as a drypowder with a dry gelatin binder in an approximate 11:2 weight ration. Aminor amount of magnesium stearate is added as a lubricant. The mixtureis formed into 240–270 mg tablets (80–90 mg of active pyrrolidineoxadiazole compound per tablet) in a tablet press.

Formulation 2—Capsules

A pyrrolidine oxadiazole compound of formula I is admixed as a drypowder with a starch diluent in an approximate 1:1 weight ratio. Themixture is filled into 250 mg capsules (125 mg of active pyrrolidineoxadiazole compound per capsule).

Formulation 3—Liquid

A pyrrolidine oxadiazole compound of formula I, sucrose and xanthan gumare blended, passed through a No. 10 mesh U.S. sieve, and then mixedwith a previously prepared solution of microcrystalline cellulose andsodium carboxymethyl cellulose (11:89) in water. Sodium benzoate,flavor, and color are diluted with water and added with stirring.Sufficient water is then added.

Formulation 4—Tablets

A pyrrolidine oxadiazole compound of formula I is admixed as a drypowder with a dry gelatin binder in an approximate 1:2 weight ratio. Aminor amount of magnesium stearate is added as a lubricant. The mixtureis formed into 450–900 mg tablets (150–300 mg of active pyrrolidineoxadiazole compound) in a tablet press.

Formulation 5—Injection

A pyrrolidine oxadiazole compound of formula I is dissolved in abuffered sterile saline injectable aqueous medium to provide asatisfactory concentration.

Example 84 Biological Assays

The compounds according to formula I may be subjected to the followingassays:

a) In Vitro Competition Binding Assay with Scintillating Proximity Assay(Pharmaceutical Manufacturing International, 1992, p. 49–53 by Cook, N.D. et al)

This assays allows to determine the affinity of the test compounds forthe OT receptor. Membranes from HEK293EBNA cells expressing the hOTreceptor were resuspended in buffer containing 50 mM Tris-HCl, pH 7.4, 5mM MgCl2 and 0.1% BSA (w/v). The membranes (2–4 μg) were mixed with 0.1mg wheat-germ aglutinin (WGA) SPA bead (type A) and 0.2 nM of theradiolabel [¹²⁵I]-OVTA (OVTA being Ornithin Vasoactive and is ananalogue of OT for competition binding experiments). Non-specificbinding was determined in the presence of 1 μM Oxytocin. The total assayvolume was 100 μl. The plates (Corning® NBS plate) were incubated atroom temperature for 30 min and counted on a Mibrobeta plate counter.The tests compounds were used in concentrations of 30 μM, 10 μM, 1 μM,300 nM, 100 nM, 10 nM, 1 nM, 100 pM, 10 pM. The competition binding datawere analysed using the iterative, non-linear, curve-fitting program,“Prism”.

The binding affinities to the oxytocin receptor of the pyrrolidinederivatives claimed in the formula I were assessed using the abovedescribed in vitro biological assay. Representative values for someexample compounds are given in Table I below. The values refer to thebinding affinity (IC₅₀; μM) of the example compounds according toformula I to the Oxytocin receptor.

TABLE 1 Binding affinity human OT-R Structure IUPAC-Name IC₅₀ (μM)

(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(3-meth-yl-1,2,4-oxadiazol-5-yl)-3-pyr-rolidinoneO-methyloxime 0.088

(3EZ,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)car-bonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyr-rolidinoneO-methyloxime 0.021

(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(1,3,4-oxa-diazol-2-yl)-3-pyrrolidinoneO-methyl-oxime 0.211

(3E,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)car-bonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyr-rolidinoneO-methyloxime 0.023

(3Z,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)car-bonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyr-rolidinoneO-methyloxime 0.009

(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(1RS)-1-hy-droxypropyl]-1,2,4-oxadiazol-5-yl)-3-pyr-rolidinoneO-methyloxime 0.006

(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[2-oxo-2-(1-pyr-rolidinyl)ethyl]-1,2,4-oxa-diazol-5-yl]-3-pyrrolidinoneO-meth-yloxime 0.007

(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-hy-droxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyr-rolidinoneO-methyloxime 0.011

(3EZ,5S)-5-[5-(1-acetyl-4-piperidinyl)-1,2,4-oxa-diazol-3-yl]-1-([1,1′-biphenyl]-4-ylcar-bonyl)-3-pyrrolidinoneO-methyloxime 0.002

N-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcar-bonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxa-diazol-5-yl}methyl)acetamide0.003

According to a preferred embodiment, the compounds display bindingaffinities (IC₅₀ (μM)) of less 0.40 μM, more preferred of less than 0.1μM.

b) Functional Assay No. 1: Inhibition of Ca²⁺-mobilization by FLIPR(Fluorescent Imaging Plate Reader)

FLIPR is a machine for fluorescence imaging using a laser that iscapable of illuminating a 96-well plate and a means of simultaneouslyreading each well thus enabling rapid measurements on a large number ofsamples.

This assay intends to show the inhibition of the OT/OT-R mediatedcalcium mobilisation—being necessary to cause uterine contractions—byusing test compounds of formula (I).

Preparing the plates: FLIPR-plates were pre-coated with PLL(Poly-L-Lysine) 10 μg/ml+0.1% gelatine to attach the HEK (HumanEmbryonic Kidney) cells for 30 min up to 2 days at 37° C. The cells wereplated out into 96-well plates (60000 cells/well).

Labelling with fluo-4: 50 μg fluo-4 (fluorescent marker) were dissolvedin 20 μl pluronic acid (20% in DMSO). The dissolved fluo-4 was thendiluted in 10 ml DMEM (Dubecco's Minimal Essential Medium-F12 mediumwithout FCS (Fetal Calf Serum). The medium was removed from the plates,followed by one wash with DMEM-F12 medium. Now, 100 μl of the DMEM-F12medium containing fluo-4 were added and the cells incubated for 1–1.5 h(CHO-cells), and 1.5–2 h (HEK-cells). The cells now contain thefluorescent marker.

Buffer: 145 mM NaCl, 5 mM KCl, 1 mM MgCl₂, 10 mM Hepes, 10 mM Glucose,EGTA (Ethylene-bis oxyethylene nitrilo tetraacetic acid). Adjust to pH7.4.

Performance of the assay: A minimum of 80 μl/well of antagonists (5×) inthe above buffer (1×) were prepared (96-well plates). The antagonistswere added to the well-plates at different concentrations (30 μM, 10 μM,1 μM, 300 nM, 100 nM, 10 nM, 1 nM, 100 pM, 10 pM).

OT is added at a concentration of 40 nM.

The fluorescent market being sensitive to the amount of Ca²⁺ mobilizedwithin the cell may be quantified by the FLIPR machine.

The activities of the pyrrolidine derivatives according to formula Iwere assessed using the above described in vitro biological assay.Representative values for some example compounds are given in Table 2below. The values refer to the capacity of the example compoundsaccording to formula I to effectively antagonize oxytocin-inducedintracellular Ca²⁺-mobilization mediated by the Oxytocin receptor.

TABLE 2 Inhibition of Ca²⁺ mobilization, hOT-R Structure IUPAC-Name IC₅₀(μM)

(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(3-meth-yl-1,2,4-oxadiazol-5-yl)-3-pyr-rolidinoneO-methyloxime 0.004

(3EZ,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)car-bonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyr-rolidinoneO-methyloxime 0.012

(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(1,3,4-oxa-diazol-2-yl)-3-pyrrolidinoneO-meth-yloxime 0.220

(3EZ,5S)-1-[(2′-chloro[1,1′-biphenyl]-4-yl)car-bonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyr-rolidinoneO-methyloxime 0.001

(3Z,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)car-bonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyr-rolidinoneO-methyloxime 0.004c) Functional Assay No. 2: Inhibition of IP3 (InositolTri-Phosphate)-Synthesis in HEK/EBNA-OTR Cells

This assay intends to show the inhibition of the OT/OT-R mediated IP3synthesis—being necessary to cause uterine contractions—by using testcompounds of formula (I).

Stimulation of the cells: HEK/EBNA OTR (rat or human) cells were platedout into costar 12-well plates, and equilibrated for 15–24 h with[³H]-inositol radiolabel in medium without inositol supplement, with 1%FCS (0.5 ml/well). 4 μCi/ml were used. After this, the medium containingthe label was aspirated. Then was added DMEM (without FCS, inositol), 20mM Hepes (4-(2-hydroxyethyl)-1-piperazine-ethane-sulphonic acid), 1mg/ml BSA containing 10 mM LiCl (freshly prepared), for 10–15 min at 37°C. The agonist (i.e. oxytocin used at a concentration of 10 nM) and theantagonists (i.e. the tests compounds of formula (I) used in aconcentration of 10 μM, 1 μM, 300 nM, 100 nM, 10 nM, 1 nM, 100 pM, 10pM, 3 pM) were added for the time required (15–45 min), followed byaspiration of the medium. Due to the antagonization of the OT receptor,the radiolabeled inositol is phosphorylated to yield IP3, the amount ofthe radiolabeled IP3 may be determined through the ensuing work-up. Thereaction was stopped with 1 ml STOP-solution (i.e. 0.4 M perchloricacid), and let sit for 5–10 min at Room Temperature. Then, 0.8 ml weretransferred into tubes containing 0.4 ml of neutralizing solution (0.72M KOH/0.6M KHCO₃), and the tubes vortexed and kept in the cold at leastfor 2 h.

Separation of IP's: The samples were spun in a table top centrifuge at3000–4000 rpm for 15 min. 1 ml of the supernatant was transferred to newtubes containing 2.5 ml H₂O. Packed resin (0.8 ml) was equilibrated with20 ml H₂O, and the whole samples poured onto the chromatography columns,thus separating the mixture. To discard free inositol, two washes with10 ml H₂O were carried out.

Elution of total IP's: The elution was achieved using 3 ml 1M ammoniumformate/0.1M formic acid. The eluant was collected in scintillationcounting tubes, followed by addition of 7 ml of scintillation liquid.The amount of IP3 is determined by a scintillating counter.

d) In Vivo Model for Inhibition of Uterine Contractions

The assay intends to show the biological effect of tested compounds inan in vivo model of preterm labor, premature birth.

Non-pregnant Charles River CD(SD) BR female rats (9–10 weeks old,200–250 g) were treated at 18 and 24 hours before the experiment with250 μg/kg, i.p. diethylstilbestrol (DES). For the assay, the animal wasanaesthetised by urethane (1.75 g/kg, i.p.) and placed on anhomeothermic operating table. The trachea was isolated and cannulatedwith a suitable polyethylene (PE) tubing. A midline incision at thehypogastrium level was made and one uterine horn exposed, its cephalicend cannulated with a PE240 tubing and, after filling the internalcavity with 0.2 ml of sterile physiological saline, connected to a“Gemini” amplifying/recording system via a P231D Gould Statham pressuretransducer, in, order to measure said pressure. For the i.v. route ofadministration of the test compounds, one jugular vein was isolated andcannulated with a PE60 tubing connected to a butterfly needle to allowthe administration by a dispensing syringe. In the case of intraduodenaladministration of the test compounds, the duodenum was isolated andsimilarly cannulated through a small incision in its wall. One carotidartery was also isolated and cannulated with PE60 catheter and connectedto a suitable syringe for blood sample collection (see below). After astabilization period, the same dose of oxytocin was repeatedly injectedintravenously at 30-min intervals. When comparable contractile responsesof the uterus to the selected dose of oxytocin were obtained, the testcompound was administered at a concentration of 0.3; 1; 3; 10 mg/kg (5ml/kg infusion; i.v) and 30 mg/kg (7.5 ml/kg infusion; iv), as well asconcentrations of 3 and 10 mg/kg (5 ml/kg; per os), 30 mg/kg (7.5 ml/kg;per os) and also 60 mg/kg (10 ml/kg; per os.). Further injections of thesame dose of oxytocin were then made for a suitable time after treatmentto assess inhibitory effects of the compounds under study. Thecontractile response of the uterus to oxytocin was quantified bymeasuring the intrauterine pressure and the number of contractions.

A total of six animals is forming one group which is treated with agiven test compound at a given concentration (see above).

The effect of the test compounds were evaluated by comparing pre- andpost-treatment pressure values. In addition, at 2, 30, 90 and 210minutes after test compound administration, a 0.5-ml blood sample waswithdrawn from the cannulated carotid artery of each experimentalanimal. Plasma was obtained by standard laboratory procedure and theresulting samples were stored at −20° C.

The activities of the pyrrolidine derivatives claimed in the formula Iwere assessed using the above described in vivo biological assay.Representative values for one example compound are given in Table 3below. The values refer to the capacity of the example compoundaccording to formula I to effectively antagonize oxytocin-induceduterine contractions in the rat.

TABLE 3 Route of % Reduction administration of Uterine Dose StructureIUPAC-Name Vehicle Contraction (mg/kg)

(3Z,5S)-1-[(2′-meth-yl[1,1′-biphenyl]-4-yl)car-bonyl]-5-(3-meth-yl-1,2,4-oxadiazol-5-yl)-3-pyr-rolidinoneO-meth-yloxime Intravenous; NP3S5 ml/kg infusion Intravenous; NP3S;7.5ml/kg infusion −21.5 ± 7.3−44.6 ± 7.1−58.0 ±5.9−67.2 ± 10.1−80.3 ± 5.10.3131030

(3Z,5S)-1-([1,1′-bi-phenyl]-4-ylcarbonyl)-5-[3-(2-hy-droxyethyl)-1,2,4-oxa-diazol-5-yl]-3-pyr-rolidinoneO-meth-yloxime subcutaneous;NP3S;5 ml/kg −13.2 ± 5.6−30.2 ± 1.1−39.7 ±7.2−57.5 ± 8.6 131030

(3Z,5S)-1-([1,1′-bi-phenyl]-4-ylcarbonyl)-5-{5-[(di-methylamino)methyl]-1,2,4-oxa-diazol-3-yl}-3-pyr-rolidinoneO-meth-yloxime oral; NP3S;5 ml/kg oral; NP3S;6 ml/kg −11.1 ± 1.3−42.1 ±2.9−49.5 ± 6.1−74.4 ± 4.2 131030

1. A compound according to formula I:

a geometrical isomer thereof, an optically active form thereof, anenantiomer thereof, a diastereomer thereof, a racemate thereof, or apharmaceutically acceptable salt thereof, wherein: A is selected fromthe group consisting of —(C═O)—, —(C═O)—O—, —SO₂—, —SO₂NH—, and —CH₂—; Bis an unsubstituted or substituted oxadiazole or unsubstituted orsubstituted thiadiazole ring; R¹ is selected from the group consistingof C₁–C₆-alkyl, C₂–C₆-alkenyl, C₂–C₆-alkynyl, aryl, heteroaryl, C₁–C₆alkyl aryl, and C₁–C₆ alkyl heteroaryl, wherein R¹ can form with the Oatom to which it is attached a 3–8 membered, saturated or unsaturatedheterocyclic ring which may contain 1–2 further heteroatoms selectedfrom the group consisting of N, S and O and which is optionally fusedwith an aryl, heteroaryl or 3–8 membered saturated or unsaturatedcycloalkyl ring; R² is selected from the group consisting ofC₁–C₆-alkyl, C₂–C₆-alkenyl, C₂–C₆-alkynyl, aryl, heteroaryl,heteroarylalkyl, 3–8-membered cycloalkyl, acyl, C₁–C₆-alkyl aryl, andC₁–C₆-alkyl heteroaryl, wherein said cycloalkyl or aryl or heteroarylgroups may be fused with 1–2 further cycloalkyl or aryl or heteroarylgroups; R³, R⁴, R⁵ and R⁶ are independently selected from the groupconsisting of hydrogen, halogen, C₁–C₆-alkyl and C₁–C₆-alkoxy.
 2. Thecompound according to claim 1, wherein R¹ is selected from the groupconsisting of H and a —C₁–C₆ alkyl group.
 3. The compound according toclaim 1, wherein A is —(C═O)—.
 4. The compound according to claim 1,wherein R² is an aryl or a heteroaryl group.
 5. The compound accordingto claim 4, wherein R² is a phenyl group.
 6. The compound according toclaim 5, wherein said phenyl group is substituted by a phenyl group. 7.The compound according to claim 1, wherein B is an oxadiazole of formulaIIa or IIb:

wherein R⁷ is selected from the group comprising of hydrogen, sulfonyl,amino, C₁–C₆-alkyl, C₂–C₆-alkenyl, and C₂–C₆-alkynyl, wherein saidalkyl, alkenyl, alkynyl chains may be interrupted by a heteroatomselected from N, O or S, aryl, heteroaryl, saturated 3–8-memberedcycloalkyl, unsaturated 3–8-membered cycloalkyl, heterocycloalkyl,wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups maybe fused with 1–2 further cycloalkyl, heterocycloalkyl, aryl orheteroaryl group, an acyl moiety, C₁–C₆-alkyl aryl, C₁–C₆-alkylheteroaryl, C₁–C₆-alkenyl aryl, C₁–C₆-alkenyl heteroaryl, C₁–C₆-alkynylaryl, C₁–C₆-alkynyl heteroaryl, C₁–C₆-alkyl cycloalkyl, C₁–C₆-alkylheterocycloalkyl, C₁–C₆-alkenyl cycloalkyl, C₁–C₆-alkenylheterocycloalkyl, C₁–C₆-alkynyl cycloalkyl, C₁–C₆-alkynylheterocycloalkyl, alkoxycarbonyl, aminocarbonyl, C₁–C₆-alkyl carboxy,C₁–C₆-alkyl acyl, aryl acyl, heteroaryl acyl, C₃–C₈-(hetero)cycloalkylacyl, C₁–C₆-alkyl acyloxy, C₁–C₆-alkyl alkoxy, C₁–C₆-alkylalkoxycarbonyl, C₁–C₆-alkyl aminocarbonyl, C₁–C₆-alkyl acylamino,acylamino, C₁–C₆-alkyl ureido, C₁–C₆-alkyl carbamate, C₁–C₆-alkyl amino,C₁–C₆-alkyl ammonium, C₁–C₆-alkyl sulfonyloxy, C₁–C₆-alkyl sulfonyl,C₁–C₆-alkyl sulfinyl, C₁–C₆-alkyl sulfanyl, C₁–C₆-alkyl sulfonylamino,C₁–C₆-alkyl aminosulfonyl, hydroxy and halogen.
 8. The compoundaccording to claim 7, wherein R⁷ is selected from the group consistingof a sulfonyl moiety, an amino moiety, a C₁–C₆-alkyl group,C₂–C₆-alkenyl group, C₂–C₆-alkynyl group, aryl group, heteroaryl group,3–8-membered cycloalkyl group, optionally containing at least oneheteroatom selected from the group consisting of N, O, and S,C₁–C₆-alkyl aryl, C₁–C₆-alkyl heteroaryl, C₁–C₆-alkenyl aryl,C₁–C₆-alkenyl heteroaryl, alkoxycarbonyl, carboxylic amide, C₁–C₆-alkylcarbonyl, C₁–C₆-arylcarbonyl, C₁–C₆-heteroarylcarbonyl, andC₄–C₈-cycloalkylcarbonyl, said groups substituted by at least onesulfonyl moiety or amino moiety.
 9. The compound according to claim 8,wherein R⁷ is selected from the group consisting of a C₁–C₆-alkyl amino,heterocycloalkyl, C₁–C₆-alkyl heterocycloalkyl, aminocarbonyl,C₁–C₆-alkylamino carbonyl, C₁–C₆ alkyl acyl amino, C₁–C₆ alkyl sulfonyland C₁–C₆-alkyl.
 10. The compound according to claim 9, wherein R⁷ isselected from the group consisting of dimethyl aminomethyl,2-(dimethylamino)ethyl, 1-methyl-3-piperidinyl and4-(acetyl-1-piperazinyl)methyl.
 11. The compound according to claim 1,wherein B is an isoxadiazole of formula III or IV:

wherein X is O or S; R⁸ is a hydrogen, C₁–C₆-alkyl, C₂–C₆-alkenyl,C₂–C₆-alkynyl, aryl, heteroaryl, saturated 3–8-membered cycloalkyl,unsaturated 3–8-membered cycloalkyl, optionally containing 1 to 3heteroatoms selected from the group consisting of N, O and S, an acylmoiety, C₁–C₆-alkyl aryl, C₁–C₆-alkyl heteroaryl, C₁–C₆-alkenyl aryl,C₁–C₆-alkenyl heteroaryl, alkoxycarbonyl, carboxylic amide,C₁–C₆-alkoxy, aryloxy, heteroaryloxy, halogen, cyano, C₁–C₆-alkylcarbonyl, arylcarbonyl, of heteroarylcarbonyl, saturatedC₄–C₈-cycloalkylcarbonyl, and unsaturated C₄–C₈-cycloalkylcarbonyl,wherein said cycloalkyl or aryl or heteroaryl groups may be fused with1–2 further cycloalkyl or aryl or heteroaryl group and wherein saidalkyl, alkenyl, alkynyl chain may be interrupted by an heteroatomselected from the group consisting of N, O and S.
 12. The compoundaccording to claim 1 wherein each of R³, R⁴, R⁵ and R⁶ is H.
 13. Thecompound according to claim 1 wherein A is —(C═O)—, R¹ is a methylgroup, R² is a biphenyl group, each of R³, R⁴, R⁵ and R⁶ is H and B isan oxadiazole ring of formulae IIa, IIb, III or IV.
 14. The compoundaccording to claim 13 wherein B is an oxadiazole ring of formula IIa orIIb.
 15. The compound according to claim 1 selected from the groupconsisting of:(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(1,3,4-oxadiazol-2-yl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-5-(3-benzyl-1,2,4-oxadiazol-5-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(3-{[(2-furylmethyl)sulfanyl]methyl}-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(2-pyridinylsulfanyl)methyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(2-thienylsulfanyl)methyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(methylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(5-methyl-3-isoxazolyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-thienylmethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(3-phenyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(3-{[(2-furylmethyl)sulfonyl]methyl}-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-5-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(RS)-hydroxy(phenyl)methyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(1RS)-1-hydroxypropyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(1S,2R)-2-hydroxycyclohexyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(3RS)-piperidinyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(2RS)-piperidinyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-[(2′-chloro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-1-{[2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-3-pyrrolidinoneO-methyloxime,(3Z,5S)-1-[(2′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-[(4′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(1,2,4-oxadiazol-3-yl)-3-pyrrolidinoneO-methyloxime,(3E,5S)-1-[(2′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime,(3E,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime,(3Z,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(phenoxymethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-phenyl-1,2,4-oxadiazol-3-yl)-3-pyrrolidinoneO-methyloxime,N-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)acetamide,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[4-(hydroxymethyl)phenyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(2-hydroxyethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(2S)-2-hydroxy-2-phenylethyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime,{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methylformamide,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(methoxymethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(2-phenoxyethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime, (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(2-methoxyethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-5-[5-(1-acetyl-4-piperidinyl)-1,2,4-oxadiazol-3-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(3-thienyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-cyclopentyl-1,2,4-oxadiazol-3-yl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(RS)-hydroxy(phenyl)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(1RS)-1-hydroxy-2-phenylethyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(1R)-1-(dimethylamino)-2-phenylethyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(3-pyridinyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(4-pyridinyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime,(3Z,5S)-5-{5-[(4-acetyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-5-[3-(1-acetyl-4-piperidinyl)-1,2,4-oxadiazol-5-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-5-{5-[(4-acetyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime,N-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-3-(1-piperidinyl)propanamide,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(3S)-1-methylpiperidinyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(3R)-1-methylpiperidinyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(6-hydroxy-3-pyridinyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime,(3Z,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(dimethylamino)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-5-{5-[(1S,2R)-1-amino-2-hydroxypropyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(3S)-piperidinyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(3R)-piperidinyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime,(3EZ,5RS)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(1-methyl-3-piperidinyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime, tert-butyl(3R)-3-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}-1-piperidinecarboxylate,4-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-2,6-piperazinedione,(3Z,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime,(3Z,5S)-1-[(2′-chloro-4′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(1-methyl-4-piperidinyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(dimethylamino)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(1-methyl-4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-5-{5-[(1S)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime,5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-N-[3-(dimethylamino)propyl]-1,2,4-oxadiazole-3-carboxamide,(3E,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(dimethylamino)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime, tert-butyl(3S)-3-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}-1-piperidinecarboxylate,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(4-methyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime,(3Z,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(4-methyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime, ethyl5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazole-3-carboxylate,(3E,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime,(3Z,5RS)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime,N-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-3-(dimethylamino)propanamide,tert-butyl4-(2-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}ethyl)-1-piperazinecarboxylate,(3EZ,5S)-1-[(2′-chloro-4′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-[(4′-fluoro-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[2-(dimethylamino)ethyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinoneO-methyloxime,2-{5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-3-yl}ethyl[(tert-butoxycarbonyl)amino]acetate,N-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-2-(dimethylamino)acetamide,(3EZ,5S)-1-[(2′-chloro-4′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-5-{5-[(1S)-1-amino-2-tert-butoxyethyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime, tert-butyl4-{5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-3-yl}-1-piperidinecarboxylate,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(1-piperazinylmethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinoneO-methyloxime, tert-butyl(4S)-4-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}-4-[(tert-butoxycarbonyl)amino]butanoate,4-{[(2S,4EZ)-2-(5-{[(tert-butoxycarbonyl)amino]methyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl,tert-butyl2-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}ethylcarbamate,2-{5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-3-yl}ethylaminoacetate,(3E,5S)-1-[(2′,4′-difluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime,(3EZ,5S)-1-[(2′,4′-difluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime,4-{[(2S,4EZ)-2-(5-{(1S)-2-tert-butoxy-1-[(tert-butoxycarbonyl)amino]ethyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl,(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-vinyl-1,2,4-oxadiazol-3-yl)-3-pyrrolidinoneO-methyloxime,4-{[(2S,4EZ)-2-(5-{(1S,2R)-2-tert-butoxy-1-[(tert-butoxycarbonyl)amino]propyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl,(3Z,5S)-1-[(2′,4′-difluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinoneO-methyloxime and tert-butyl4-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-1-piperazinecarboxylate.16. A pharmaceutical composition comprising at least one compoundaccording to claim 1 and a pharmaceutically acceptable carrier, diluentor excipient.
 17. A method of preparing a compound of formula (I), asclaimed in claim 1, wherein B is a 1,2,4-oxadiazole group of formula(IIb)

comprising: reacting XV with VII


18. A method of preparing a compound of formula (I), as claimed in claim1, wherein B is a 1,2,4-oxadiazole group of formula (IIa)

comprising: reacting V with VI


19. A method of preparing a compound of formula (I), as claimed in claim1, wherein B is a 1,3,4-oxadiazole group of formula (III) or (IV)comprising either of: reacting XVII with CDI or CS₂, or reacting XVIIIwith Tmof and P₂O₅


20. The compound according to claim 1, wherein R¹ is —CH₃.
 21. A methodfor treating preterm labor, premature birth or dysmenorrhea comprisingadministering an effective amount to a mammal in need thereof apharmaceutical composition comprising the compound according to claim 1.22. The method as claimed in claim 21, wherein the mammal is a human.23. The method as claimed in claim 21, wherein the composition isadministered in an amount effective for modulating an oxytocin receptor.24. The method as claimed in claim 23, wherein modulating oxytocinreceptor includes at least one of blocking the oxytocin receptor orantagonizing the binder of the oxytocin to a receptor.
 25. The method asclaimed in claim 21, wherein the composition is administered in anamount effective for the treatment or prevention of at least onedisorder mediated by the oxytocin receptor.
 26. The method as claimed inclaim 21, wherein the administering is carried out orally.